Methods for assessing risk of developing a viral of disease using a genetic test

ABSTRACT

This document provides methods and materials related to treating a disease. For example, this document provides methods for treating a subject&#39;s disease based on identifying the risk of progressive multifocal leukoencephalopathy PML using a genetic test.

CROSS REFERENCE

This application is a continuation of International Application No. PCT/US19/45721, which claims the benefit of U.S. Provisional Application No. 62/716,072, filed Aug. 8, 2018, and U.S. Provisional Application No. 62/716,183, filed Aug. 8, 2018, each of which is hereby incorporated by reference in its entirety.

REFERENCE TO A SEQUENCE LISTING

The instant application contains a Sequence Listing. A compact disc labeled “COPY 1—SEQUENCE LISTING” contains a computer readable form of the Sequence Listing file named 56969-701.301_SL.txt. The Sequence Listing is 154,980,352 bytes in size and was recorded on Jan. 16, 2020. The compact disc is 1 of 2 compact discs. A duplicate copy of the compact disc is labeled “COPY 2—SEQUENCE LISTING.” The compact disc and duplicate copy are identical and are hereby incorporated by reference in their entirety into the instant application.

BACKGROUND OF THE DISCLOSURE

Progressive multifocal leukoencephalopathy (PML) is a rare and potentially fatal opportunistic infection of the central nervous system that is caused by a ubiquitous polyomavirus, the JC virus (JCV). While JCV is present at very high rates in the general population, PML remains a rare disorder, albeit an important one because of the poor survival and the severe neurological sequelae, and the recently demonstrated association with a variety of useful therapies, for example, natalizumab in multiple sclerosis (MS). A number of risk factors for PML have been described but these are better viewed as necessary but not sufficient. While these risk factors are highly relevant, they do not, on their own, predict who will develop PML, since the vast majority of individuals with these risk factors will not develop the disorder. Other factors need to be considered and there is growing evidence for the role of host genetic factors in susceptibility to PML.

The ability to more accurately predict who is at risk of developing PML will be of enormous benefit in the context of drug treatment with compounds that are highly effective in their disease context (natalizumab in MS, for example) but carry a risk of a devastating disorder. There is a need to develop a companion diagnostic testing, in order to effectively exclude those that were at risk of PML, in the process reassuring those with negative tests about their dramatically reduced risk of developing PML.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In the event of a conflict between a term herein and a term incorporated by reference, the term herein controls.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings.

FIG. 1 represents an example of a gene (PRKCB) impacted by germline and acquired CNVs.

FIG. 2 represents an example of genes (TNFRSF13C and CENPM) impacted by acquired CNVs.

FIG. 3 represents an example of a gene (PKHD1) impacted by germline and acquired CNVs.

FIG. 4 represents an example of a gene (BMPR2) impacted by a CNV (homozygous and heterozygous losses).

FIG. 5 represents an example of a gene (COMMD6) impacted by a CNV (e.g., homozygous duplication).

FIG. 6 represents an example of genes (KCTD7, RABGEF1) directly and potentially impacted by a CNV (e.g., homozygous duplication).

FIG. 7 represents an example of a gene (FPR2) impacted by a CNV (e.g., homozygous duplication).

FIG. 8 represents an example of a gene (PIK3CD) impacted by a CNV (e.g., homozygous loss).

FIG. 9 represents an example of a gene (CD180) potentially impacted by an intergenic CNV gain (e.g., homozygous duplication).

FIG. 10 represents an example of a gene (VDAC1) potentially impacted by an intergenic CNV (homozygous loss).

FIG. 11 represents an example of genes (EGR1 and ETF1) potentially impacted by an intergenic CNV (homozygous loss).

FIG. 12 represents an example of a gene (ITSN2) potentially impacted by an intergenic CNV (homozygous loss).

FIG. 13 represents an example of known and/or predicted protein interactions using the String database for 21 of 43 genes (non-redundant list) reported in Table 7. The number of PML cases found to harbor variants impacting a given gene is indicated next to each gene.

FIG. 14 represents an example gene set analysis of protein-protein interactions using the String database described herein. The input gene list was 74 genes (see Table 42) and the largest network from the String database analysis output, a 24-gene network, is depicted. The genes are color-coded based on the GO pathway ID with the largest number of genes (26) that was in the top 5 GO results: GO:0006955, dark gray colored genes.

SUMMARY OF THE INVENTION

Provided herein is a method of treating a condition in a subject in need thereof, comprising: administering a therapeutically effective amount of one or more immunosuppressive medications to the subject, wherein the subject is identified as not having a high risk of developing progressive multifocal leukoencephalopathy (PML) by a genetic test. In some embodiments, the subject is identified as not having a risk of developing PML by a genetic test.

Provided herein is a method of treating a condition in a subject in need of immunosuppressive medication therapy, comprising: administering a therapeutically effective amount of one or more immunosuppressive medications to the subject, wherein the subject has a decreased risk of progressive multifocal leukoencephalopathy (PML) due to an infection of the brain by John Cunningham virus (JCV), wherein the subject's decreased risk is due to the absence of one or more genetic variations that occur at a frequency of 100% or less in a population of human subjects with PML. In some cases, the one or more genetic variations occur at a frequency of 100% or less, for example, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less, 0.08% or less, 0.06% or less, 0.04% or less, 0.02% or less, 0.01% or less, 0.005% or less, 0.002% or less, or 0.001% or less in a population of human subjects with PML. In some cases, the one or more genetic variations occur at a frequency of from 60% to 100%, from 30% to 60%, from 10% to 30%, from 5% to 10%, from 1% to 5%, from 0.5% to 1%, from 0.1% to 0.5%, from 0.05% to 0.1%, from 0.01% to 0.05%, from 0.005% to 0.01%, from 0.001% to 0.005%, or from 0.00001% to 0.001% in a population of human subjects with PML.

In some embodiments, the risk is due to the absence of one or more genetic variations that occur at a frequency of 100% or less in a population of human subjects with PML and with an immune deficiency. In some cases, the one or more genetic variations occur at a frequency of 100% or less, for example, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less, 0.08% or less, 0.06% or less, 0.04% or less, 0.02% or less, 0.01% or less, 0.005% or less, 0.002% or less, or 0.001% or less in a population of human subjects with PML and with an immune deficiency. In some cases, the one or more genetic variations occur at a frequency of from 60% to 100%, from 30% to 60%, from 10% to 30%, from 5% to 10%, from 1% to 5%, from 0.5% to 1%, from 0.1% to 0.5%, from 0.05% to 0.1%, from 0.01% to 0.05%, from 0.005% to 0.01%, from 0.001% to 0.005%, or from 0.00001% to 0.001% in a population of human subjects with PML and with an immune deficiency.

The immune deficiency can be X-linked agammaglobulinemia (XLA), common variable immunodeficiency (CVID), severe combined immunodeficiency (SCID), acquired immune deficiency syndrome (AIDS), cancers of the immune system (e.g., leukemia), immune-complex diseases (e.g., viral hepatitis), or multiple myeloma.

In some embodiments, the subject's decreased risk is due to the absence of one or more genetic variations that occur at a frequency of 100% or less in a population of human subjects with PML and without an immune deficiency. In some cases, the one or more genetic variations occur at a frequency of 100% or less, for example, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less, 0.08% or less, 0.06% or less, 0.04% or less, 0.02% or less, 0.01% or less, 0.005% or less, 0.002% or less, or 0.001% or less in a population of human subjects with PML and without an immune deficiency. In some cases, the one or more genetic variations occur at a frequency of from 60% to 100%, from 30% to 60%, from 10% to 30%, from 5% to 10%, from 1% to 5%, from 0.5% to 1%, from 0.1% to 0.5%, from 0.05% to 0.1%, from 0.01% to 0.05%, from 0.005% to 0.01%, from 0.001% to 0.005%, or from 0.00001% to 0.001% in a population of human subjects with PML and without an immune deficiency.

Provided herein is a method of treating a condition in a subject in need of immunosuppressive medication therapy, comprising: administering a therapeutically effective amount of one or more immunosuppressive medications to the subject, wherein the subject has a decreased risk of progressive multifocal leukoencephalopathy (PML) due to an infection of the brain by John Cunningham virus (JCV), and wherein the subject's decreased risk is due to the absence of one or more genetic variations that occur at a frequency of 100% or less in a population of human subjects without PML. In some cases, the one or more genetic variations occur at a frequency of 100% or less, for example, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less, 0.08% or less, 0.06% or less, 0.04% or less, 0.02% or less, 0.01% or less, 0.005% or less, 0.002% or less, or 0.001% or less in a population of human subjects without PML. In some cases, the one or more genetic variations occur at a frequency of from 60% to 100%, from 30% to 60%, from 10% to 30%, from 5% to 10%, from 1% to 5%, from 0.5% to 1%, from 0.1% to 0.5%, from 0.05% to 0.1%, from 0.01% to 0.05%, from 0.005% to 0.01%, from 0.001% to 0.005%, or from 0.00001% to 0.001% in a population of human subjects without PML.

In some embodiments, the risk is due to the absence of one or more genetic variations that occur at a frequency of 100% or less in a population of human subjects without PML and with an immune deficiency. In some cases, the one or more genetic variations occur at a frequency of 100% or less, for example, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less, 0.08% or less, 0.06% or less, 0.04% or less, 0.02% or less, 0.01% or less, 0.005% or less, 0.002% or less, or 0.001% or less in a population of human subjects without PML and with an immune deficiency. In some cases, the one or more genetic variations occur at a frequency of from 60% to 100%, from 30% to 60%, from 10% to 30%, from 5% to 10%, from 1% to 5%, from 0.5% to 1%, from 0.1% to 0.5%, from 0.05% to 0.1%, from 0.01% to 0.05%, from 0.005% to 0.01%, from 0.001% to 0.005%, or from 0.00001% to 0.001% in a population of human subjects without PML and with an immune deficiency.

In some embodiments, the risk is due to the absence of one or more genetic variations that occur at a frequency of 100% or less in a population of human subjects without PML and without an immune deficiency. In some cases, the one or more genetic variations occur at a frequency of 100% or less, for example, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less, 0.08% or less, 0.06% or less, 0.04% or less, 0.02% or less, 0.01% or less, 0.005% or less, 0.002% or less, or 0.001% or less in a population of human subjects without PML and without an immune deficiency. In some cases, the one or more genetic variations occur at a frequency of from 60% to 100%, from 30% to 60%, from 10% to 30%, from 5% to 10%, from 1% to 5%, from 0.5% to 1%, from 0.1% to 0.5%, from 0.05% to 0.1%, from 0.01% to 0.05%, from 0.005% to 0.01%, from 0.001% to 0.005%, or from 0.00001% to 0.001% in a population of human subjects without PML and without an immune deficiency.

Provided herein is a method of treating a condition in a subject in need of immunosuppressive medication therapy, comprising: administering a therapeutically effective amount of one or more immunosuppressive medications to the subject, wherein the subject has a decreased risk of progressive multifocal leukoencephalopathy (PML) due to an infection of the brain by John Cunningham virus (JCV), and wherein the risk is due to the absence of one or more genetic variations that occur at a frequency of 100% or less in a population of human subjects with an immune deficiency. In some cases, the one or more genetic variations occur at a frequency of 100% or less, for example, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less, 0.08% or less, 0.06% or less, 0.04% or less, 0.02% or less, 0.01% or less, 0.005% or less, 0.002% or less, or 0.001% or less in a population of human subjects with an immune deficiency. In some cases, the one or more genetic variations occur at a frequency of from 60% to 100%, from 30% to 60%, from 10% to 30%, from 5% to 10%, from 1% to 5%, from 0.5% to 1%, from 0.1% to 0.5%, from 0.05% to 0.1%, from 0.01% to 0.05%, from 0.005% to 0.01%, from 0.001% to 0.005%, or from 0.00001% to 0.001% in a population of human subjects with an immune deficiency.

In some embodiments, the risk is due to the absence of one or more genetic variations that occur at a frequency of 100% or less in a population of human subjects with an immune deficiency and with PML. In some embodiments, the risk is due to the absence of one or more genetic variations that occur at a frequency of 100% or less in a population of human subjects with an immune deficiency and without PML.

Provided herein is a method of treating a condition in a subject in need of immunosuppressive medication therapy, comprising: administering a therapeutically effective amount of one or more immunosuppressive medications to the subject, wherein the subject has a decreased risk of progressive multifocal leukoencephalopathy (PML) due to an infection of the brain by John Cunningham virus (JCV), and wherein the subject's decreased risk is due to the absence of one or more genetic variations that occur at a frequency of 100% or less in a population of human subjects without an immune deficiency. In some cases, the one or more genetic variations occur at a frequency of 100% or less, for example, 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.9% or less, 0.8% or less, 0.7% or less, 0.6% or less, 0.5% or less, 0.4% or less, 0.3% or less, 0.2% or less, 0.1% or less, 0.08% or less, 0.06% or less, 0.04% or less, 0.02% or less, 0.01% or less, 0.005% or less, 0.002% or less, or 0.001% or less in a population of human subjects without an immune deficiency. In some cases, the one or more genetic variations occur at a frequency of from 60% to 100%, from 30% to 60%, from 10% to 30%, from 5% to 10%, from 1% to 5%, from 0.5% to 1%, from 0.1% to 0.5%, from 0.05% to 0.1%, from 0.01% to 0.05%, from 0.005% to 0.01%, from 0.001% to 0.005%, or from 0.00001% to 0.001% in a population of human subjects without an immune deficiency.

In some embodiments, the risk is due to the absence of one or more genetic variations that occur at a frequency of 100% or less in a population of human subjects without an immune deficiency and with PML. In some embodiments, the risk is due to the absence of one or more genetic variations that occur at a frequency of 100% or less in a population of human subjects without an immune deficiency and without PML.

Provided herein is a method of treating a condition in a subject in need of immunosuppressive medication therapy, comprising: administering a therapeutically effective amount of one or more immunosuppressive medications to the subject, wherein the subject has a decreased risk of progressive multifocal leukoencephalopathy (PML) due to an infection of the brain by John Cunningham virus (JCV), wherein the subject's decreased risk is due to the absence of one or more genetic variations in the subject, wherein the one or more genetic variations have an odds ratio (OR) of 1.1 or more, and wherein the OR is: [D_(D)/D_(N)]/[N_(D)/N_(N)], wherein: D_(D) is the number of subjects in a diseased cohort of subjects with the one or more genetic variations; D_(N) the number of subjects in the diseased cohort without the one or more genetic variations; N_(D) is the number of subjects in a non-diseased cohort of subjects with the one or more genetic variations; and N_(N) is the number of subjects in the non-diseased cohort without the one or more genetic variations. In some embodiments, the subject's decreased risk is due to the absence of one or more genetic variations that has an odds ratio (OR) of at least 1.1, for example, at least 1.2, at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 15, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, at least 400, at least 450, at least 500, at least 600, at least 700, at least 800, at least 900, at least 1000, at least 1100, at least 1200, at least 1300, at least 1400, or at least 1500. In another embodiment, the subject's decreased risk is due to the absence of one or more genetic variations that has an OR of infinite wherein N_(D) is 0 (the one or more genetic variations are not found in the non-diseased cohort). In another embodiment, N_(D) can be set to 1 when calculating OR if the one or more genetic variations are not found in the non-diseased cohort. In some embodiments, the one or more immunosuppressive medications comprise natalizumab.

In some embodiments, the cohort comprises at least 100 human subjects. In some embodiments, the at least 100 human subjects comprises at least 10 human subjects with PML, at least 10 human subjects with an immune deficiency, at least 10 human subjects without an immune deficiency, at least 10 human subjects without PML, or any combination thereof. In some embodiments, the diseased cohort comprises at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 human subjects with PML, with an immune deficiency, or both. In some embodiments, the non-diseased cohort comprises at least 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 human subjects without PML, without an immune deficiency, or both. In some embodiments, the human subjects in the cohort are the same ethnicity (e.g., African ancestry, European ancestry). In some embodiments, the human subjects in the cohort are different ethnicities. In some embodiments, the human subjects in the cohort are the same gender. In some embodiments, the human subjects in the cohort are different genders. In some embodiments, the diseased cohort of subjects, the non-diseased cohort of subjects, or both cohorts of subjects are ethnically matched. In some embodiments, the diseased cohort of subjects, the non-diseased cohort of subjects, or both cohorts of subjects are not ethnically matched.

Provided herein is a method of treating a condition in a subject in need of immunosuppressive medication therapy, comprising: administering a therapeutically effective amount of one or more immunosuppressive medications to a subject with a condition, wherein the subject has a decreased risk of progressive multifocal leukoencephalopathy (PML) due to an infection of the brain by John Cunningham virus (JCV), wherein the subject's decreased risk is due to the presence of genetic sequences that do not comprise any of 2 or more genetic variations in a panel comprising the 2 or more genetic variations.

In some embodiments, the 2 or more genetic variations comprise at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100 genetic variations. In some embodiments, the genetic sequences are wild-type genetic sequences. In some embodiments, the genetic sequences are wild-type genetic sequences comprising one or more silent mutations. In some embodiments, the one or more silent mutations comprise a mutation in a non-coding region. In some embodiments, the one or more silent mutations comprise a mutation in an exon that does not result in a change to the amino acid sequence of a protein (synonymous substitution).

In some embodiments, the condition is a cancer, an organ transplant, or an autoimmune disease.

In some embodiments, the condition is an autoimmune disease.

In some embodiments, the autoimmune disease is selected from the group consisting of Addison disease, Anti-NMDA receptor encephalitis, antisynthetase syndrome, Aplastic anemia, autoimmune anemias, Autoimmune hemolytic anemia, Autoimmune pancreatitis, Behcet's Disease, bullous skin disorders, Celiac disease—sprue (gluten-sensitive enteropathy), chronic fatigue syndrome, Chronic inflammatory demyelinating polyneuropathy, chronic lymphocytic leukemia, Crohn's disease, Dermatomyositis, Devic's disease, Erythroblastopenia, Evans syndrome, Focal segmental glomerulosclerosis, Granulomatosis with polyangiitis, Graves disease, Graves' ophthalmopathy, Guillain-Barre syndrome, Hashimoto thyroiditis, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgA-mediated autoimmune diseases, IgG4-related disease, Inflammatory bowel disease, Juvenile idiopathic arthritis, Multiple sclerosis, Myasthenia gravis, myeloma, non-Hodgkin's lymphoma, Opsoclonus myoclonus syndrome (OMS), Pemphigoid, Pemphigus, pemphigus vulgaris, Pernicious anemia, polymyositis, Psoriasis, pure red cell aplasia, Reactive arthritis, Rheumatoid arthritis, Sarcoidosis, scleroderma, Sjögren syndrome, Systemic lupus erythematosus, Thrombocytopenic purpura, Thrombotic thrombocytopenic purpura, Type I diabetes, Ulcerative colitis, Vasculitis (e.g., vasculitis associated with anti-neutrophil cytoplasmic antibody), Vitiligo, and combinations thereof.

In some embodiments, the autoimmune disease is multiple sclerosis or Crohn's disease. In some embodiments, the autoimmune disease is multiple sclerosis. In some embodiments, the multiple sclerosis is a relapsing form of multiple sclerosis. In some embodiments, the multiple sclerosis is relapsing-remitting multiple sclerosis (RRMS). In some embodiments, the multiple sclerosis is primary progressive multiple sclerosis (PPMS). In some embodiments, the multiple sclerosis is secondary progressive multiple sclerosis (SPMS).

In some embodiments, the one or more immunosuppressive medications comprise a glucocorticoid, cytostatic, antibody, drug acting on immunophilins, interferon, opioid, TNF binding protein, mycophenolate, small biological agent, small molecule, organic compound, or any combination thereof.

In some embodiments, the one or more immunosuppressive medications comprise A2aR antagonist, Akt inhibitor, anti CD20, Anti-amyloidotic (AA) Agent, anti-CD37 protein therapeutic, anti-CTLA4 mAb, Anti-CXCR4, anti-huCD40 mAb, anti-LAG3 mAb, anti-PD-1 mAb, anti-PD-L1 agent, anti-PD-L1 agent, anti-PD-L1 mAb, anti-TGFb mAb, anti-TIGIT mAb, anti-TIM-3 mAb, Aurora kinase inhibitor, Bcl-2 Inhibitor, bifunctional fusion protein targeting TGFb and PD-L1, bispecific anti-PD-1 and anti-LAG3 mAb, CD1d ligand, CD40 agonist, Complement C5a inhibitor, CSF1R inhibitor, EZH2 inhibitor, FGFR3 inhibitor, FGFR4 inhibitor, FGFrR3 inhibitor, glucocorticoid-induced tumor necrosis factor receptor-related gene [GITR] agonist, glutaminase inhibitor, Human monoclonal antibody against IL-12, ICOS agonist, IDO1 inhibitor, IL2 mutein, IL2 receptor agonist, MEK inhibitor, multitargeted receptor tyrosine kinase inhibitor, neutrophil elastase inhibitor, Notch Inhibitor, p38 MAPK inhibitor, PD-1 inhibitor, recombinant human Flt3L, ROCK inhibitor, selective sphingosine-1-phosphate receptor modulator, Src kinase inhibitor, TLR4 agonist, TLR9 agonist, or any combination thereof.

In some embodiments, the one or more immunosuppressive medications comprise abatacept (e.g. ORENCIA), abrilumab, acalabrutinib, adalimumab, adrenocorticotropic hormone, agatolimod sodium, AJM300, aldesleukin, alefacept, alemtuzumab, alisertib, alvespimycin hydrochloride, alvocidib, ambrisentan (e.g. LETAIRIS), aminocamptothecin, amiselimod, anakinra, andecaliximab, andrographolides (a botanical medicinal herb also known as IB-MS), anifrolumab, antithymocyte Ig, apatinib, apelisib, asparaginase, atacicept, atezolizumab, avelumab, azacitidine, azathioprine, bafetinib, baminercept, baricitinib, basiliximab, becatecarin, begelomab, belatacept, belimumab, bemcentinib, bendamustine, bendamustine (e.g. bendamustine hydrochloride), betalutin with lilotomab, bevacizumab, BIIB033, BIIB059, BIIB061, bimekizumab, binimetinib, bleomycin, blinatumomab, BNZ-1, bortezomib (e.g. VELCADE), brentuximab vedotin, bryostatin 1, bucillamine, buparlisib, busulfan, canakinumab, capecitabine, carboplatin, carfilzomib, carmustine, cediranib maleate, cemiplimab, ceralifimod, cerdulatinib, certolizumab (e.g. certolizumab pegol), cetuximab, chidamide, chlorambucil, CHS-131, cilengitide, cirmtuzumab, cisplatin, cladribine, clazakizumab, clemastine, clioquinol, corticosteroids, cyclophosphamide, cyclosporine, cytarabine, cytotoxic chemotherapy, daclizumab, dalfampridine (e.g. AMPYRA), daprolizumab pegol, daratumumab, dasatinib, defactinib, defibrotide, denosumab, dexamethasone, diacerein, dimethyl fumarate, dinaciclib, diroximel fumarate (e.g. VUMERITY), doxorubicin, doxorubicin (e.g. doxorubicin hydrochloride), durvalumab, duvelisib, duvortuxizumab, eculizumab (e.g. SOLIRIS), efalizumab, eftilagimod alpha, EK-12 (a neuropeptide combination of metenkefalin and tridecactide), elezanumab, elotuzumab (e.g. EMPLICITI), encorafenib, enfuvirtida (e.g. FUZEON), entinostat, entospletinib, enzastaurin, epacadostat, epirubicin, epratuzumab, eritoran tetrasodium, etanercept, etoposide, etrolizumab, everolimus, evobrutinib, filgotinib, fingolimod (e.g. fingolimod hydrochloride), firategrast, fludarabine, fluorouracil, fontolizumab, forodesine hydrochloride, fostamatinib, galunisertib, ganetespib, ganitumab, gemcitabine, gemtuzumab ozogamicin, gerilimzumab, glasdegib, glassia, glatiramer acetate, glembatumumab vedotin, glesatinib, golimumab (e.g. SIMPONI), guadecitabine, hydrocortisone, hydroxychloroquine sulfate, hydroxyurea, ibritumomab tiuxetan, ibrutinib, ibudilast, idarubicin, idebenone, idelalisib, ifosfamide, iguratimod, imatinib, imexon, IMU-838, infliximab, inotuzumab ozogamicin, interferon alfa-2, interferon beta-1a, interferon beta-1b, interferon gamma-1, ipilimumab, irofulven, isatuximab, ispinesib, itacitinib, ixazomib, lapatinib, laquinimod, laromustine, ld-aminopterin, leflunomide, lenalidomide, lenvatinib, letrozole (e.g. FEMARA), levamisole, levocabastine, lipoic acid, lirilumab, lonafamib, lumiliximab, maraviroc (e.g. SELZENTRY), masitinib, mavrilimumab, melphalan, mercaptopurine, methotrexate, methoxsalen, methylprednisone, milatuzumab, mitoxantrone, mizoribine, mocetinostat, monalizumab, mosunetuzumab, motesanib diphosphate, moxetumomab pasudotox, muromonab-CD3, mycophenolate mofetil (e.g. mycophenolate mofetil hydrochloride), mycophenolic acid, namilumab, natalizumab, navitoclax, neihulizumab, nerispirdine, neurovax, niraparib, nivolumab, obatoclax mesylate, obinutuzumab, oblimersen sodium, ocrelizumab, ofatumumab, olokizumab, opicinumab, oprelvekin, osimertinib, otelixizumab, oxaliplatin, oxcarbazepine, ozanimod, paclitaxel, pacritinib, palifermin, panobinostat, pazopanib, peficitinib, pegfilgrastim (e.g. NEULASTA), peginterferon beta-1a, pegsunercept (peg stnf-ri), pembrolizumab, pemetrexed, penclomedine, pentostatin, perifosine, pevonedistat, pexidartinib, picoplatin, pidilizumab, pivanex, pixantrone, pleneva, plovamer acetate, polatuzumab vedotin, pomalidomide, ponatinib, ponesimod, prednisone/prednisolone, pyroxamide, R-411, ravulizimab-cwvz (e.g. (ULTOMIRIS), recombinant it-12, relatlimab, rhigf-1, rhigm22, rigosertib, rilonacept, ritonavir (e.g. NORVIR), rituximab, ruxolitinib, SAR442168/PRN2246, sarilumab, secukinumab, selumetinib, simvastatin, sintilimab, siplizumab, siponimod (e.g. MAYZENT), sirolimus (rapamycin), sirukumab, sitravatinib, sonidegib, sorafenib, sotrastaurin acetate, sunitinib, sunphenon epigallocatechin-gallate, tabalumab, tacrolimus (e.g. tacrolimus anhydrous), talabostat mesylate, talacotuzumab, tanespimycin, tegafur/gimeracil/oteracil, temozolomide, temsirolimus, tenalisib, terameprocol, teriflunomide, thalidomide, thiarabine, thiotepa, tipifarnib, tirabrutinib, tislelizumab, tivozanib, tocilizumab, tofacitinib, TR-14035, tregalizumab, tremelimumab, treosulfan, ublituximab, umbralisib, upadacitinib, urelumab, ustekinumab, varlilumab, vatelizumab, vedolizumab, veliparib, veltuzumab, venetoclax, vinblastine, vincristine, vinorelbine ditartrate, visilizumab, vismodegib, vistusertib, voriconazole (e.g. VFEND), vorinostat, vosaroxin, ziv-aflibercept, or any combination thereof.

In some embodiments, the one or more immunosuppressive medications comprise 2B3-201, 3PRGD2, 4SC-202, 506U78, 6,8-bis(benzylthio)octanoic acid, 68Ga-BNOTA-PRGD2, 852A, 89Zr-DFO-CZP, ABBV-257, ABL001, ABP 501, ABP 710, ABP 798, ABT-122, ABT-199, ABT-263, ABT-348, ABT-494, ABT-555, ABT-874, ABX-1431 HCl, ACP-196, ACP-319, ACT-128800, ACY-1215, AD 452, Ad-P53, ADCT-301, ADCT-402, ADL5859, ADS-5102, AFX-2, AGEN1884, AGEN2034, AGS67E, AIN457, AK106-001616, ALD518, ALKS 8700, ALT-803, ALT-803, ALX-0061, ALXN1007, ALXN6000, AMD3100, AMG 108, AMG 319, AMG 357, AMG 570, AMG 592, AMG 714, AMG 719, AMG 827, AMP-110, AP1903, APL A12, AP0866, APX005M, AQ4N, AR-42, ARN-6039, ARQ 531, ARRY-371797, ARRY-382, ARRY-438162, ART-I02, ART621, ASK8007, ASNO02, ASP015K, ASP1707, ASP2408, ASP2409, ASP5094, AT-101, AT7519M, AT9283, ATA188, ATN-103, ATX-MS-1467, AVL-292, AVP-923, AZD4573, AZD5672, AZD5991, AZD6244, AZD6738, AZD9056, AZD9150, AZD9567, AZD9668, B-701, BAF312, BAY1830839, BBI608, BCD-054, BCD-055, BCD-063, BCD-089, BCD-100, BCD-132, BCD-145, BEZ235, BG00012, BG9924, BGB-3111, BGB-A333, BGG492, BHT-3009, BI 655064, BI 695500, BI 695501, BI 836826, BI-1206, MBR 796 BS, BIIB017, BIIB023, BIIB057, BIIB061, BIIL 284 BS, BLZ945, BMMNC, BMN 673, BMS-247550, BMS-582949, BMS-817399, BMS-936558, BMS-936564, BMS-945429, BMS-986104, BMS-986142, BMS-986156, BMS-986195, BMS-986205, BMS-986213, BMS-986226, BMS-986251, BNC105P, BOW015, BP1001, BT061, BTT-1023, C105, CAL-101, CAM-3001, CAT-8015, CB-839, CBL0137, CC-1088, CC-115, CC-122, CC-292, CC100, CCI-779, CCX 354-C, CDKI AT7519, CDP323, CDP6038, CDP870, CDX-1127, CDX-301, CE-224535, CF101, CFZ533, CGP 77116, CH-1504, CH-4051, CHR-5154, CHS-0214, CK-2017357, CLAG-M, CLR 131, CMAB008, CMP-001, CNF2024 (BIIB021), CNM-Au8, CNTO 1275, CNTO 136, CNTO 148, CNTO 6785, CP-195543, CP-461, CpG 7909, CPI-1205, CR6086, CRx-102, CS-0777, CS1002, CT-011, CT-1530, CT-P10, CV301, CX-3543, DAC-HYP, DCDT2980S, DI-B4, DPA-714 FDG, DS-3032b, DT2219ARL, DTRM-505, DTRM-555, DTRMWXHS-12, DWP422, E6011, E7449, EK-12, ELND002, ENIA11, EOC202, ETBX-011, F81L10, FBTA05, FEDAA1106 (BAY85-8101), FGF401, FKB327, FPA008, FR104, FS118, FTY720, G100, GCS-100, GDC-0199, GDC-0853, GEH120714, GLPG0259, GLPG0634, GNbAC1, GNKG168, GP2013, GP2015, GRN163L, GS-1101, GS-5745, GS-9219, GS-9820, GS-9876, GS-9901, GSK1223249, GSK1827771, GSK2018682, GSK21110183, GSK239512, GSK2618960, GSK2831781, GSK2982772, GSK3117391, GSK3152314A, GSK3196165, GSK3358699, GSK706769, GW-1000-02, GW274150, GW406381, GW856553, GZ402668, HCD122, HE3286, HL2351, HL237, hLL1-DOX (IMMU-115), HLX01, HM71224, HMPL-523, HSC835, HZT-501, ICP-022, IDEC-C2B8, ILV-094, IMGN529, IMMU-114, IMO-2125, INCAGN02385, INCB018424, INCB028050, INCB039110, INCB047986, INCMGA00012, INNO-406, INT131, INT230-6, INVAC-1, IPI-145, IPX056, ISF35, ISIS 104838, ITF2357, JCARH125, JHL1101, JNJ 38518168, JNJ-39758979, JNJ-40346527, JNJ-63723283, JS001, JTE-051, JTX-2011, KB003, KD025, KPT-330, KW-2449, KW-2478, KX2-391, L-778123, LAG525, LAM-002A, LBEC0101, LBH589, LFB-R603, LMB-2, LX3305, LY2127399, LY2189102, LY2439821, LY3009104, LY3090106, LY3300054, LY3321367, LY3337641, M2951, M7824, M923, MBG453, MBP8298, MBS2320, MD1003, MDG013, MDV9300, MDX-1100, MDX-1342, MDX-1411, ME-401, MEDI-522, MEDI-538, MEDI-551, MEDI4920, MGA012, MGCD0103, MGD007, MIS416, MK-0873, MK-4280, MK-4827, MK-8457, MK-8808, MK0359, MK0457, MK0752, MK0782, MK0812, MK2206, MLN1202, MLTA3698A, MM-093, MN-122, MN-166, monoclonal antibody M-T412, monoclonal antibody mono-dgA-RFB4, MOR00208, MOR103, MORAb-022, MP-435, MP470, MRC375, MRG-106, MS-533, MSB11022, MSC2490484A, MT-1303, MT-3724, MTIG7192A, MTRX1011A, NBI-5788, NC-503, NI-0101, NI-071, NIS793, NKTR-214, NNC 0141-0000-0100, NNC 0151-0000-0000, NNC0109-0012, NNC0114-0000-0005, NNC0114-0006, NNC0142-0002, NNCO215-0384, NNC109-0012, NOX-A12, NT-KO-003, NU100, OMB157, OMP-313M32, ON01910 Na, ONO-2506P0, ONO-4641, ONTAK, OPB 31121, OSI-461, OTS167IV, P1446A-05, PBF-509, PBRO6, PCI 32765, PCI-24781, PD 0360324, PDA001, PDR001, PF-04171327, PF-04236921, PF-04308515, PF-04629991, PF-05280586, PF-06342674, PF-06410293, PF-06438179, PF-06650833, PF-06651600, PF-06835375, PG-760564, PH-797804, PLA-695, PLX3397, PLX5622, POL6326, PRO131921, PRO283698, PRTX-100, PS-341, PTL201, R(+)XK469, R788, RAD001, RC18, REGN1979, REGN3767, REGN2810, REGN4659, RFT5-SMPT-dgA, RG2077, RGB-03, RGI-2001, RHB-104, RNS60, RO5045337, RO7123520, Rob 803, RPC1063, RWJ-445380, S 55746, SAIT101, SAN-300, SAR245409, SB-681323, SB683699, SBI-087, SC12267 (45C-101), SCH 727965, SCIO-469, SD-101, SG2000, SGN-40, SHC014748M, SHR-1210, SHR0302, SHR1020, SJG-136, SKI-O-703, SMP-114, SNS-032, SNS-062, SNX-5422, SPARC1103 I, SPC2996, SSR150106, STA 5326 mesylate, Sunpharma1505, SyB L-0501, Sym022, Sym023, SYN060, T-614, T0001, TA-650, TAB08, TAK-715, TAK-783, TAK-901, TGR-1202, TH-302, TL011, TMI-005, TMP001, TNFa Kinoid, TP-0903, TRU-015, TRU-016, TSR-022, TSR-033, TSR-042, TXA127, VAY736, VP-16, VSN16R, VX-509, VX-702, VX-745, VX15/2503, XCEL-MC-ALPHA, XL228, XL844, XmAb13676, XmAb5574, XOMA 052, YRA-1909, Z102, ZEN003365, or any combination thereof.

In some embodiments, the one or more immunosuppressive medications comprise interferon beta-1a, interferon beta-1b, glatiramer acetate, peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone, rituximab, natalizumab, daclizumab, ocrelizumab, diroximel fumarate, siponimod or any combination thereof.

In some embodiments, the subject has not taken the one or more immunosuppressive medications. In some embodiments, the subject has taken the one or more immunosuppressive medications. In some embodiments, the subject is taking the one or more immunosuppressive medications.

In some embodiments, the one or more immunosuppressive medications comprise natalizumab (e.g., TYSABRI). In some embodiments, at least about 10 mg of the natalizumab is administered, for example, at least about 10 mg, at least about 15 mg, at least about 20 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, at least about 150 mg, at least about 200 mg, at least about 250 mg, or at least about 300 mg of the natalizumab is administered. In some embodiments, at least about 10 mg of the natalizumab is administered via intravenous infusion. In some embodiments, at least about 10 mg of the natalizumab is administered via intravenous infusion in four weeks. In some embodiments, about 100 mg to about 500 mg of the natalizumab is administered, for example, about 100 mg to about 200 mg, about 100 mg to about 300 mg, about 100 mg to about 400 mg, about 100 mg to about 500 mg, about 200 mg to about 300 mg, about 200 mg to about 400 mg, about 200 mg to about 500 mg, about 300 mg to about 400 mg, about 300 mg to about 500 mg, or about 400 mg to about 500 mg of the natalizumab is administered. In some embodiments, about 100 mg to about 500 mg of the natalizumab is administered via intravenous infusion. In some embodiments, about 100 mg to about 500 mg of the natalizumab is administered via intravenous infusion in four weeks. In some embodiments, about 300 mg of the natalizumab is administered. In some embodiments, about 300 mg of the natalizumab is administered via intravenous infusion. In some embodiments, about 300 mg of the natalizumab is administered via intravenous infusion in four weeks. In some embodiments, at least about 10 mg of the natalizumab is administered via intravenous infusion in six weeks. In some embodiments, at least about 10 mg of the natalizumab is administered via intravenous infusion in eight weeks. In some embodiments, about 100 mg to about 500 mg of the natalizumab is administered via intravenous infusion in six weeks. In some embodiments, about 100 mg to about 500 mg of the natalizumab is administered via intravenous infusion in eight weeks. In some embodiments, about 300 mg of the natalizumab is administered via intravenous infusion in six weeks. In some embodiments, about 300 mg of the natalizumab is administered via intravenous infusion in eight weeks.

In some embodiments, the one or more immunosuppressive medications comprise dimethyl fumarate. In some embodiments, about 100 mg to about 500 mg of the dimethyl fumarate is administered, for example, about 100 mg to about 200 mg, about 100 mg to about 300 mg, about 100 mg to about 400 mg, about 100 mg to about 500 mg, about 200 mg to about 300 mg, about 200 mg to about 400 mg, about 200 mg to about 500 mg, about 300 mg to about 400 mg, about 300 mg to about 500 mg, or about 400 mg to about 500 mg of the dimethyl fumarate is administered. In some embodiments, about 120 mg of the dimethyl fumarate is administered. In some embodiments, about 240 mg of the dimethyl fumarate is administered.

In some embodiments, the one or more immunosuppressive medications comprise diroximel fumarate. In some embodiments, the one or more immunosuppressive medications comprise diroximel fumarate. In some embodiments, about 100 mg to about 500 mg of the diroximel fumarate is administered, for example, about 100 mg to about 200 mg, about 100 mg to about 300 mg, about 100 mg to about 400 mg, about 100 mg to about 500 mg, about 200 mg to about 300 mg, about 200 mg to about 400 mg, about 200 mg to about 500 mg, about 300 mg to about 400 mg, about 300 mg to about 500 mg, or about 400 mg to about 500 mg of the diroximel fumarate is administered. In some embodiments, about 400, 410, 420, 430, 440, 450, 460, 462, 470, 480, 490 or 500 mg of the diroximel fumarate is administered.

In some embodiments, the one or more immunosuppressive medications comprise fingolimod. In some embodiments, about 0.01 mg to about 5 mg of the fingolimod is administered, for example, about 0.01 mg to about 2 mg, about 0.01 mg to about 3 mg, about 0.01 mg to about 4 mg, about 0.01 mg to about 5 mg, about 0.1 mg to about 2 mg, about 0.1 mg to about 3 mg, about 0.1 mg to about 4 mg, about 0.1 mg to about 5 mg, about 0.2 mg to about 3 mg, about 0.2 mg to about 4 mg, about 0.2 mg to about 5 mg, about 0.3 mg to about 4 mg, about 0.3 mg to about 5 mg, about 0.4 mg to about 5 mg, about 0.1 mg to about 0.2 mg, about 0.1 mg to about 0.3 mg, about 0.1 mg to about 0.4 mg, about 0.1 mg to about 0.5 mg, about 0.2 mg to about 0.3 mg, about 0.2 mg to about 0.4 mg, about 0.2 mg to about 0.5 mg, about 0.3 mg to about 0.4 mg, about 0.3 mg to about 0.5 mg, about 0.4 mg to about 0.5 mg, or about 0.4 mg to about 0.6 mg of the fingolimod is administered. In some embodiments, about 0.25 mg or 0.5 mg of the fingolimod is administered.

In some embodiments, the one or more immunosuppressive medications comprise rituximab. In some embodiments, about 100 mg to about 1000 mg of the rituximab is administered, for example, about 100 mg to about 200 mg, about 100 mg to about 300 mg, about 100 mg to about 400 mg, about 100 mg to about 500 mg, about 100 mg to about 600 mg, about 100 mg to about 700 mg, about 100 mg to about 800 mg, about 100 mg to about 900 mg of the rituximab is administered. The dose may be by weight or a fixed dose. In some embodiments, about 250 mg/m², 375 mg/m², 500 mg/m², 500 mg, or 1000 mg of the rituximab is administered. In some embodiments, about 250 mg/m², 375 mg/m², 500 mg/m², 500 mg, or 1000 mg of the rituximab is administered every week, every 2 weeks, every 4 weeks, every 8 weeks, or every 6 months. In some embodiments, about 250 mg/m², 375 mg/m², 500 mg/m², 500 mg, or 1000 mg of the rituximab is administered every 8 weeks or every 6 months for treating MS. The total dose cab be from about 50 and 4000 mg, for example, from about 75 and 3000 mg, from about 100 and 2000 mg, from about 100 and 1000 mg, from about 150 and 1000 mg, or from about 200 and 1000 mg, including doses of about 200, 300, 400, 500, 600, 700, 800, 900, 1000 mg, and 2000 mg. These doses may be given as a single dose or as multiple doses, for example, two to four doses. Such doses may be done by infusions, for example.

In some embodiments, the one or more immunosuppressive medications comprise siponimod. In some embodiments, about 0.1 mg to about 5 mg of the siponimod is administered. In some embodiments, about 1 mg or about 2 mg of the siponimod is administered. In some embodiments, about 1 mg or about 2 mg of the siponimod is administered to a subject with a CYP2C9*1/*3 or CYP2C9*2/*3 genotype.

In some embodiments, the subject does not have one or more genetic variations associated with a risk of developing PML. In some embodiments, the subject does not have one or more genetic variations associated with a high risk of developing PML.

In some embodiments, the genetic test comprises detecting one or more genetic variations associated with a risk of developing PML in a polynucleic acid sample from the subject. In some embodiments, the genetic test comprises detecting one or more genetic variations associated with a high risk of developing PML in a polynucleic acid sample from the subject.

In some embodiments, the one or more genetic variations comprise a point mutation, polymorphism, single nucleotide polymorphism (SNP), single nucleotide variation (SNV), translocation, insertion, deletion, amplification, inversion, interstitial deletion, copy number variation (CNV), structural variation (SV), loss of heterozygosity, or any combination thereof.

In some embodiments, the one or more genetic variations disrupt or modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48.

Provided herein is a method of treating a condition in a subject in need of natalizumab, interferon beta-1a, interferon beta-1b, glatiramer acetate, peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone, rituximab, daclizumab, ocrelizumab, diroximel fumarate or siponimod therapy, comprising: administering a therapeutically effective amount of natalizumab, interferon beta-1a, interferon beta-1b, glatiramer acetate, peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone, rituximab, daclizumab, ocrelizumab, diroximel fumarate or siponimod to the subject, wherein the subject is identified as not having one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48.

Provided herein is a method of reducing a risk of a subject developing progressive multifocal leukoencephalopathy (PML) comprising administering a therapeutically effective amount of natalizumab to the subject, wherein the subject is identified as not having one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48.

In some embodiments, the condition is multiple sclerosis.

In some embodiments, the condition is Crohn's disease.

Provided herein is a method of treating multiple sclerosis comprising administering natalizumab, interferon beta-1a, interferon beta-1b, glatiramer acetate, peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone, rituximab, daclizumab, ocrelizumab, diroximel fumarate or siponimod to a subject with multiple sclerosis, wherein the subject is identified as not having one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48.

Provided herein is a method of treating Crohn's disease comprising administering natalizumab, interferon beta-1a, interferon beta-1b, glatiramer acetate, peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone, rituximab, daclizumab, ocrelizumab, diroximel fumarate or siponimod to a subject with Crohn's disease, wherein the subject is identified as not having one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48.

Provided herein is a method of treating multiple sclerosis comprising testing a subject with multiple sclerosis for the presence of one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48, determining that the subject does not have the one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48, and administering natalizumab to the subject that was determined not to have the one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48.

Provided herein is a method of treating Crohn's disease comprising testing a subject with Crohn's disease for the presence of one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48, determining that the subject does not have the one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48, and administering natalizumab to the subject that was determined not to have the one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48.

Provided herein is a method of reducing a risk of a subject developing progressive multifocal leukoencephalopathy (PML) comprising testing a subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48, determining that the subject has at least one of the one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48, and advising against administering natalizumab, interferon beta-1a, interferon beta-1b, glatiramer acetate, peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone, rituximab, daclizumab, ocrelizumab, diroximel fumarate or siponimod to the subject that was determined to have at least one of the one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48.

In some embodiments, the subject has multiple sclerosis.

In some embodiments, the subject has Crohn's disease.

Provided herein is a method of treating multiple sclerosis comprising testing a subject with multiple sclerosis for the presence of one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48, determining that the subject has at least one of the one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48, and advising against administering natalizumab to the subject that was determined to have at least one of the one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48.

Provided herein is a method of treating Crohn's disease comprising testing a subject with Crohn's disease for the presence of one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48, determining that the subject has at least one of the one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48, and advising against administering natalizumab to the subject that was determined to have at least one of the one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48.

In some embodiments, the advising comprises advising that administering natalizumab, interferon beta-1a, interferon beta-1b, glatiramer acetate, peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone, rituximab, daclizumab, ocrelizumab, diroximel fumarate or siponimod is contraindicated.

In some embodiments, the advising comprises advising that administering natalizumab, interferon beta-1a, interferon beta-1b, glatiramer acetate, peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone, rituximab, daclizumab, ocrelizumab, diroximel fumarate or siponimod increases the risk of the subject developing progressive multifocal leukoencephalopathy (PML)

In some embodiments, the advising comprises advising that administering natalizumab, interferon beta-1a, interferon beta-1b, glatiramer acetate, peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone, rituximab, daclizumab, ocrelizumab, diroximel fumarate or siponimod is a factor that increases the risk of the subject developing progressive multifocal leukoencephalopathy (PML).

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene according to Table 13.

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene according to Table 14.

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene according to Table 15.

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene according to Table 16.

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene according to Table 17.

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene according to Table 18.

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene selected from the group consisting of ALG12, AP3B1, ASH1L, ATL2, ATM, ATR, BACH1, BLM, CHD7, CLCN7, CR2, CX3CR1, DOCK2, DOCKS, EHF, EPG5, FAS, FUK, GFI1, GOLGB1, GTPBP4, HIVEP1, HIVEP2, HIVEP3, IFIH1, IGLL1, IL10, IL12B, IL17F, ITK, ITSN2, JAGN1, KITLG, LRBA, LYST, MALT1, MAVS, MCEE, NHEJ1, NOD2, NRIP1, ORAI1, PGM3, PIK3CD, PLCG2, PNP, POLE, PRF1, RBCK1, RBFOX1, RNASEL, RTEL1, SALL2, SHARPIN, SNAP29, STIM2, STXBP2, TAP1, TBC1D16, TCIRG1, TICAM1, TMEM173, TNFRSF10A, TTC7A, VPS13B, and combinations thereof.

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene selected from the group consisting of ACD, ADGRL2, AIRE, ATG5, ATG7, BLK, BRD4, C3, C7, CBA, CSB, C9, CAMLG, CCBE1, CCZ1, CD22, CD36, CD37, CD5, CD72, CFH, CFHR1, CFHR2, CFHR3, CFHR4, CFHR5, CFTR, CHD2, CLEC16A, CLPB, COPA, CTC1, DNAJC21, EGF, ERCC6L2, FAT4, FCER2, HERCS, HERC6, ICAM1, IFI35, IFIT1, IFIT3, IL4, ITSN1, KMT2D, KRAS, LRRK2, MASP2, MBL2, MCM5, MDC1, MFN2, MLH1, MMP9, MOGS, MON1A, MON1B, MSH2, MSHS, MX1, MX2, MYSM1, NBAS, NCF1, NCF2, NCF4, NFATS, NLRP2, NLRX1, NOD1, OAS1, OAS2, OAS3, ORC4, PARN, PEPD, PINK1, PLAU, PLAUR, PLCG1, PLD1, PLEKHM1, PLK1, PLXNB1, PRRC2A, RABSA, RABSB, RAD50, RANBP2, RELA, RLTPR, RNF125, RPSA, RSAD2, SAMD9, SAMD9L, SERPINA1, SERPINB2, SMARCAL1, SMURF2, SRP54, TBC1D17, TCN2, TEK, TFPI, TMC8, TP53AIP1, TRAF3IP2, USB1, USP3, VEGFA, WASHC5, WRAP53, and XAF1.

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene selected from the group consisting of PLCG2, RBCK1, EPG5, IL17F, SHARPIN, PRF1, JAGN1, TAP1, POLE, LRBA, EHF, IL12B, ATL2, NHEJ1, LYST, HIVEP1, AP3B1, TNFRSF10A, PIK3CD, PNP, MCEE, DOCK2, ALG12, and combinations thereof.

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene selected from the group consisting of PLCG2, IFIH1, TCIRG1, IGLL1, MAVS, SHARPIN, CHD7, CX3CR1, LRBA, HIVEP3, RNASEL, and combinations thereof.

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene selected from the group consisting of SHARPIN, RTEL1, PGM3, TMEM173, CLCN7, MAVS, ORAI1, RBFOX1, MALT1, GFI1, DOCK2, ATM, SNAP29, TICAM1, GTPBP4, BACH1, STXBP2, FAS, GOLGB1, FUK, IL10, ITK, STIM2, ASH1L, TBC1D16, LYST, SALL2, CHD7, BLM, NOD2, IGLL1, TTC7A, KITLG, ATR, ATM, CR2, HIVEP2, ITSN2, DOCKS, VPS13B, NRIP1, and combinations thereof.

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene selected from the group consisting of SHARPIN, IFIH1, PLCG2, CHD7, and combinations thereof.

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene selected from the group consisting of PLCG2, POLE, LRBA, EPG5, SHARPIN, and combinations thereof.

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene selected from the group consisting of PLCG2, RBCK1, EPG5, IL17F, SHARPIN, PRF1, JAGN1, TAP1, POLE, LRBA, EHF, IL12B, ATL2, NHEJ1, LYST, HIVEP1, AP3B1, TNFRSF10A, PIK3CD, PNP, MCEE, DOCK2, ALG12, FCN2, LY9 and PRAM1.

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene selected from the group consisting of FCN2, LY9 and PRAM1

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene selected from the group consisting of AIRE, ATM, C8B, CFHR2, DNASE1L3, DNER, FCN2, FCN3, GFI1, HIVEP3, IFIH1, IGLL1, LIG1, LRBA, LY9, MCM5, MDC1, NQO2, PKHD1, PLCG2, PRAM1, SERPINA1, STXBP2, TAP1 and TCIRG1.

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene selected from the group consisting of AIRE, ATM, C8B, CFHR2, DNASE1L3, DNER, FCN2, FCN3, GFI1, HIVEP3, IGLL1, LIG1, LRBA, LY9, MCM5, MDC1, NQO2, PKHD1, PRAM1, SERPINA1, and TAN.

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene selected from the group consisting of IGLL1, MDC1, STXBP2, FCN2, IGLL1, MCM5 and IFIH1.

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene selected from the group consisting of PRAM1, ATM, TAP1, PLCG2, FCN3, DNER, SERPINA1 and LRBA.

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene selected from the group consisting of IGLL1, MDC1, STXBP2, PRAM1, ATM, FCN2, IGLL1, MCM5, IFIH1, TAP1, PLCG2, FCN3, DNER, SERPINA1 and LRBA.

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene selected from the group consisting of PRAM1, HIVEP3 and TCIRG1.

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene selected from the group consisting of LY9, LIG1, PKHD1, AIRE, GFI1, CFHR2, NQO2, PRAM1, C8B, DNASE1L3, PLCG2, HIVEP3 and TCIRG1.

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene selected from the group consisting of PKHD1, LY9, CFHR2, NQO2, AIRE, IGLL1, TCIRG1, ATM, MDC1, PRAM1, FCN2, STXBP2 and PLCG2.

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene selected from the group consisting of TAP1, GFI1, IGLL1, MCM5, IFIH1, FCN3, SERPINA1

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene selected from the group consisting of PLCG2, CHD7, IFIH1, AP3B1, EPG5, PIK3CD, LRBA, SHARPIN, and combinations thereof.

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene selected from the group consisting of PKHD1, LY9, CFHR2, NQO2, AIRE, TCIRG1, ATM, MDC1, PRAM1, FCN2, STXBP2, PLCG2, TAP1, GFI1, IGLL1, MCM5, IFIH1, FCN3 and SERPINA1.

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene selected from the group consisting of LY9, PKHD1, AIRE, CFHR2, NQO2, IGLL1, PRAM1, MDC1, FCN2, STXBP2, TCIRG1 and PLCG2.

In some embodiments, the testing comprises testing the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene selected from the group consisting of LIG1, MCM5, GFI1, IFIH1, IGLL1, ATM, TAP1, FCN3, LRBA and SERPINA1.

In some embodiments, the subject is identified as not having a risk of developing progressive multifocal leukoencephalopathy (PML) by a genetic test. In some embodiments, the subject is identified as not having a high risk of developing progressive multifocal leukoencephalopathy (PML) by a genetic test.

In some embodiments, the testing comprises assaying a polynucleic acid sample from the subject for the one or more genetic variations.

In some embodiments, the one or more genetic variations result in a loss of function of the corresponding gene.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of gene numbers (GNs) GN1-GN765.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of gene numbers (GNs) 1-156 (in Table 3).

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of gene numbers (GNs) in Table 6.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of gene numbers (GNs) GN491-GN492 in Table 29.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of gene numbers (GNs) GN493-GN762 in Table 31.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of gene numbers (GNs) GN763-GN765 in Table 48.

In some embodiments, the corresponding gene comprises a gene selected from Tables 34-40, 42, 45A, 45B, 45C, 48, 50A, 50B and 51-62.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of PLCG2, RBCK1, EPG5, IL17F, SHARPIN, PRF1, JAGN1, TAP1, POLE, LRBA, EHF, IL12B, ATL2, NHEJ1, LYST, HIVEP1, AP3B1, TNFRSF10A, PIK3CD, PNP, MCEE, DOCK2 and ALG12 (see Table 13).

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of PLCG2, RBCK1, EPG5, IL17F, SHARPIN, PRF1, JAGN1, TAP1, POLE, LRBA, EHF, IL12B, ATL2, NHEJ1, LYST, HIVEP1, AP3B1, TNFRSF10A, PIK3CD, PNP, MCEE, DOCK2, ALG12, FCN2, LY9 and PRAM1.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of FCN2, LY9 and PRAM1.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of AIRE, ATM, C8B, CFHR2, DNASE1L3, DNER, FCN2, FCN3, GFI1, HIVEP3, IFIH1, IGLL1, LIG1, LRBA, LY9, MCM5, MDC1, NQO2, PKHD1, PLCG2, PRAM1, SERPINA1, STXBP2, TAP1 and TCIRG1.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of AIRE, ATM, C8B, CFHR2, DNASE1L3, DNER, FCN2, FCN3, GFI1, HIVEP3, IGLL1, LIG1, LRBA, LY9, MCM5, MDC1, NQO2, PKHD1, PRAM1, SERPINA1, and TAN.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of IGLL1, MDC1, STXBP2, FCN2, IGLL1, MCM5 and IFIH1.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of PRAM1, ATM, TAP1, PLCG2, FCN3, DNER, SERPINA1 and LRBA.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of IGLL1, MDC1, STXBP2, PRAM1, ATM, FCN2, IGLL1, MCM5, IFIH1, TAP1, PLCG2, FCN3, DNER, SERPINA1 and LRBA.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of LY9, LIG1, PKHD1, AIRE, GFI1, CFHR2, NQO2, C8B, DNASE1L3 and PLCG2.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of PRAM1, HIVEP3 and TCIRG1.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of LY9, LIG1, PKHD1, AIRE, GFI1, CFHR2, NQO2, PRAM1, C8B, DNASE1L3, PLCG2, HIVEP3 and TCIRG1.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of PKHD1, LY9, CFHR2, NQO2, AIRE, IGLL1, TCIRG1, ATM, MDC1, PRAM1, FCN2, STXBP2 and PLCG2.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of TAP1, GFI1, IGLL1, MCM5, IFIH1, FCN3, SERPINA1.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of PKHD1, LY9, CFHR2, NQO2, AIRE, TCIRG1, ATM, MDC1, PRAM1, FCN2, STXBP2, PLCG2, TAP1, GFI1, IGLL1, MCM5, IFIH1, FCN3 and SERPINA1.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of LY9, PKHD1, AIRE, CFHR2, NQO2, IGLL1, PRAM1, MDC1, FCN2, STXBP2, TCIRG1 and PLCG2.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of LIG1, MCM5, GFI1, IFIH1, IGLL1, ATM, TAP1, FCN3, LRBA and SERPINA1.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of LY9, PKHD1, AIRE, CFHR2, NQO2, IGLL1, PRAM1, MDC1, FCN2, STXBP2, TCIRG1, PLCG2, LIG1, MCM5, GFI1, IFIH1, IGLL1, ATM, TAP1, FCN3, LRBA and SERPINA1.

In some embodiments, the one or more genetic variations are encoded by a sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to SEQ ID NOs 1-172 or SRN1-SRN363, with 100% sequence identity to SEQ ID NOs 1000-1329, or with at least 80% and less than 100% sequence identity to GN1-GN490, or complements thereof.

In some embodiments, the one or more genetic variations are encoded by a sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to SEQ ID NOs 1-172, 2200-2203 or SRN1-SRN366, with 100% sequence identity to SEQ ID NOs 1000-1329, 3000-3274, or with at least 80% and less than 100% sequence identity to GN1-GN765, or complements thereof.

In some embodiments, the one or more genetic variations are encoded by a sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to SEQ ID NOs 2200-2203 or SRN364-SRN366, with 100% sequence identity to SEQ ID NOs 3000-3274, or with at least 80% and less than 100% sequence identity to GN491-GN765, or complements thereof.

In some embodiments, the one or more genetic variations are encoded by a sequence with at 100% sequence identity to SEQ ID NOs 3300-3351, 3400-3467 or 3500-3526.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a CNV with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to SEQ ID NOs 1-172, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a CNV with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to SEQ ID NOs 2200-2203, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a CNV sub-region (SRN) with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to SRN1-SRN363, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a CNV sub-region (SRN) with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to SRN364-SRN366, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a single nucleotide variation (SNV) with a sequence of any one of SEQ ID NOs: 1000-1329, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a single nucleotide variation (SNV) with a sequence of any one of SEQ ID NOs: 3000-3274, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a single nucleotide variation (SNV) with a sequence of any one of SEQ ID NOs: 3300-3351, 3400-3467, 3500-3526, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a sequence with at least 80% and less than 100% sequence identity to GN1-GN490, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a sequence with at least 80% and less than 100% sequence identity to GN491-GN765, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a single nucleotide variation (SNV) with a sequence of any one of SEQ ID NO: 1000, 1001, 1002, 1009, 1010, 1011, 1012, 1014, 1016, 1017, 1019, 1020, 1028, 1032, 1033, 1034, 1035, 1036, 1037, 1040, 1041, 1043, 1051, 1054, 1056, 1057, 1058, 1059, 1061, 1062, 1063, 1066, 1068, 1069, 1070, 1071, 1073, 1074, 1075, 1076, 1077, 1078, 1080, 1082, 1084, 1090, 1092, 1098, 1099, 1100, 1101, 1104, 1107, 1114, 1116, 1118, 1121, 1122, 1123, 1125, 1126, 1127, 1128, 1129, 1130, 1131, 1133, 1135, 1136, 1137, 1138, 1142, 1146, 1147, 1148, 1150, 1152, 1154, 1157, 1160, 1161, 1165, 1166, 1167, 1168, 1169, 1171, 1174, 1175, 1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1193, 1194, 1200, 1201, 1202, 1203, 1204, 1208, 1219, 1220, 1221, 1222, 1226, 1227, 1228, 1229, 1230, 1231, 1232, 1235, 1239, 1247, 1248, 1249, 1250, 1251, 1252, 1254, 1255, 1256, 1259, 1260, 1261, 1263, 1264, 1266, 1267, 1273, 1278, 1279, 1283, 1284, 1286, 1287, 1289, 1290, 1291, 1299, 1300, 1301, 1304, 1311, 1327 or 1328 (see Tables 7 and 8), or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a single nucleotide variation (SNV) with a sequence of any one of SEQ ID NO: 3000-3274, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a single nucleotide variation (SNV) with a sequence of any one of SEQ ID NO: 1011, 1020, 1028, 1032, 1034, 1035, 1036, 1040, 1056, 1069, 1073, 1077, 1101, 1114, 1123, 1125, 1126, 1127, 1135, 1142, 1146, 1147, 1148, 1152, 1154, 1157, 1167, 1174, 1184, 1193, 1194, 1203, 1208, 1221, 1222, 1229, 1235, 1252, 1255, 1256, 1259, 1260, 1261, 1263, 1273, 1278, 1279, 1284, 1287, 1289, 1299 or 1311 (see Table 7), or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a single nucleotide variation (SNV) with a sequence of any one of SEQ ID NO: 1000, 1001, 1002, 1009, 1010, 1012, 1014, 1016, 1017, 1019, 1033, 1037, 1041, 1043, 1051, 1054, 1057, 1058, 1059, 1061, 1062, 1063, 1066, 1068, 1070, 1071, 1074, 1075, 1076, 1078, 1080, 1082, 1084, 1090, 1092, 1098, 1099, 1100, 1104, 1107, 1116, 1118, 1121, 1122, 1128, 1129, 1130, 1131, 1133, 1136, 1137, 1138, 1146, 1147, 1150, 1152, 1160, 1161, 1165, 1166, 1168, 1169, 1171, 1175, 1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1200, 1201, 1202, 1204, 1219, 1220, 1226, 1227, 1228, 1230, 1231, 1232, 1239, 1247, 1248, 1249, 1250, 1251, 1252, 1254, 1264, 1266, 1267, 1278, 1279, 1283, 1286, 1290, 1291, 1300, 1301, 1304, 1327 or 1328 (see Table 8), or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a single nucleotide variation (SNV) with a sequence of any one of SEQ ID NO: 3300-3351, 3400-3467 or 3500-3526.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr16:81942175 A>G, chr2:163136505 C>G, chr11:67818269 G>A, chr22:23917192 G>T, chr20:3846397 C>T, chr8:145154222, G>A chr8:61654298 T>A, chr3:39323163 A>C, chr4:151199080 G>A, chr1:42047208 C>G, chr2:163124051 C>T, chr1:182554557 C>T, chr8:145154824 A>C, chr20:62305450 C>T, chr22:23915745 G>A, chr6:83884161 C>G, chr11:108202772 G>T, chr5:138856923 C>T, chr16:1510535 C>T, chr20:3843027 C>A, chr12:122064788 G>GT, chr16:7714909 C>T, chr18:56401523 C>T, chr1:92946625 G>C, chr5:169081453 G>C, chr11:108117787 C>T, chr22:21235389 A>G, chr19:4817657 C>T, chr10:1060218 G>A, chr21:30698953 T>G, chr9:304628 G>A, chr19:7712287 G>C, chr10:90771767 G>A, chr3:121415370 T>C, chr16:70503095 A>G, chr1:206945738 C>T, chr5:156593120 C>T, chr4:27019452 C>T, chr1:155317682 C>T, chr17:77926526 C>T, chr1:235840495 G>T, chr14:21993359 G>A, chr8:61757805 C>T, chr15:91306241 G>A, chr16:50741791 C>T, chr22:23915583 T>C, chr2:47205921 C>T, chr12:88900891 C>A, chr3:142281353 C>G, chr11:108123551 C>T, chr1:207641950 C>T, chr6:143092151 T>C, chr2:24431184 C>T, chr2:24432937 C>T, chr9:312134 G>A, chr8:100205255 G>A, chr21:16339852 T>C, and any combination thereof (see Tables 14 and 15).

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr16:81942175 A>G, chr2:163136505 C>G, chr11:67818269 G>A, chr22:23917192 G>T, chr20:3846397 C>T, chr8:145154222, G>A chr8:61654298 T>A, chr3:39323163 A>C, chr4:151199080 G>A, chr1:42047208 C>G, chr2:163124051 C>T, chr1:182554557 C>T, and any combination thereof (see Table 14).

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr8:145154824 A>C, chr20:62305450 C>T, chr22:23915745 G>A, chr6:83884161 C>G, chr11:108202772 G>T, chr5:138856923 C>T, chr16:1510535 C>T, chr20:3843027 C>A, chr12:122064788 G>GT, chr16:7714909 C>T, chr18:56401523 C>T, chr1:92946625 G>C, chr5:169081453 G>C, chr11:108117787 C>T, chr22:21235389 A>G, chr19:4817657 C>T, chr10:1060218 G>A, chr21:30698953 T>G, chr9:304628 G>A, chr19:7712287 G>C, chr10:90771767 G>A, chr3:121415370 T>C, chr16:70503095 A>G, chr1:206945738 C>T, chr5:156593120 C>T, chr4:27019452 C>T, chr1:155317682 C>T, chr17:77926526 C>T, chr1:235840495 G>T, chr14:21993359 G>A, chr8:61757805 C>T, chr15:91306241 G>A, chr16:50741791 C>T, chr22:23915583 T>C, chr2:47205921 C>T, chr12:88900891 C>A, chr3:142281353 C>G, chr11:108123551 C>T, chr1:207641950 C>T, chr6:143092151 T>C, chr2:24431184 C>T, chr2:24432937 C>T, chr9:312134 G>A, chr8:100205255 G>A, chr21:16339852 T>C, and any combination thereof (see Table 15).

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr1:196759282, C>T, chr4:126412634, C>G, chr10:75673748, A>C, chr6:30675830, T>A, chr6:30680721, G>A, chr12:56385915, GGGA>G, chr18:57103126, G>A, chr3:171321023, C>T, chr1:59131311, G>T, chr22:31008867, T>C, chr2:74690378, C>T, chr17:7592168, C>G, chr2:74690039, G>A, chr12:113448288, A>G, chr17:76130947, G>T, chr2:15674686, T>C, chr2:15607842, T>C, chr14:94847262, T>A, chr4:126412154, G>A, chr22:37271882, T>C, chr20:44640959, G>A, chr17:8138569, C>G, chr12:113357237, G>C, chr12:113357209, G>A, chr11:60893235, C>T, chr12:113357442, G>A, chr5:40964852, A>C, chr14:35497285, T>C, chr19:55494157, G>A, and any combination thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr11:72145307, C>G, chr7:30491421, G>T, chr6:30673403, A>G, chr19:44153248, T>C, chr17:43555253, A>G, chr2:188349523, A>G, chr1:57409459, C>A, chr4:126241248, C>G, chr5:39311336, A>T, chr17:76129619, C>T, chr4:110929301, T>C, chr3:11402163, G>A, chr16:67694044, C>T, chr19:10395141, G>A, chr6:106740989, T>C, chr1:183532364, T>A, chr22:35806756, G>A, chr4:110865044, G>C, chr4:110864533, C>T, chr4:126238090, G>T, chr4:110932508, C>A, chr6:31605016, T>C, chr7:92733766, C>A, chr18:29645930, A>T, and any combination thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr21:45708278, G>A, chr11:108106443, T>A, chr1:57409459, C>A, chr1:196918605, A>G, chr3:58191230, G>T, chr2:230579019, G>A, chr9:137779251, G>A, chr1:27699670, AG>A, chr1:92946625, G>C, chr1:42047208, C>G, chr2:163136505, C>G, chr22:23915583, T>C, chr22:23915745, G>A, chr19:48643270, C>T, chr4:151793903, T>C, chr1:160769595, AG>A, chr22:35806756, G>A, chr6:30673359, T>G, chr6:3015818, G>A, chr6:51798908, C>T, chr16:81942175, A>G, chr19:8564523, T>G, chr14:94847262, T>A, chr19:7712287, G>C, chr6:32814942, C>T, chr6:32816772, C>A and chr11:67818269, G>A.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr22:23915745, G>A, chr6:30673359, T>G, chr19:7712287, G>C, chr9:137779251, G>A, chr22:23915583, T>C, chr22:35806756, G>A and chr2:163136505, C>G. In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr19:8564523, T>G, chr11:108106443, T>A, chr6:32816772, C>A, chr6:32814942, C>T, chr16:81942175, A>G, chr1:27699670, AG>A, chr2:230579019, G>A, chr14:94847262, T>A and chr4:151793903, T>C.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr22:23915745, G>A, chr6:30673359, T>G, chr19:7712287, G>C, chr19:8564523, T>G, chr11:108106443, T>A, chr9:137779251, G>A, chr22:23915583, T>C, chr22:35806756, G>A, chr2:163136505, C>G, chr6:32816772, C>A, chr6:32814942, C>T, chr16:81942175, A>G, chr1:27699670, AG>A, chr2:230579019, G>A, chr14:94847262 and T>A, chr4:151793903, T>C.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr1:160769595, AG>A, chr19:48643270, C>T, chr6:51798908, C>T, chr21-45708278-G-A, chr1:92946625, G>C, chr1:196918605, A>G, chr6:3015818, G>A, chr1:57409459, C>A, chr3:58191230, G>T and chr16:81942175, A>G.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr19:8564523, T>G, chr1:42047208, C>G and chr11:67818269, G>A

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr1:160769595, AG>A, chr19:48643270, C>T, chr6:51798908, C>T, chr21-45708278-G-A, chr1:92946625, G>C, chr1:196918605, A>G, chr6:3015818, G>A, chr19:8564523, T>G, chr1:57409459, C>A, chr3:58191230, G>T, chr16:81942175, A>G, chr1:42047208, C>G and chr11:67818269, G>A.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr6:51798908, C>T, chr1:160769595, AG>A, chr1:196918605, A>G, chr6:3015818, G>A, chr21-45708278-G-A, chr22:23915745, G>A, chr11:67818269, G>A, chr11:108106443, T>A, chr6:30673359, T>G, chr19:8564523, T>G, chr9:137779251, G>A, chr19:7712287, G>C and chr16:81942175, A>G.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr6:32816772, C>A, chr6:32814942, C>T, chr1:92946625, G>C, chr22:23915583, T>C, chr22:35806756, G>A, chr2:163136505, C>G, chr1:27699670, AG>A and chr14:94847262, T>A.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr6:51798908, C>T, chr1:160769595, AG>A, chr1:196918605, A>G, chr6:3015818, G>A, chr21-45708278-G-A, chr22:23915745, G>A, chr11:67818269, G>A, chr11:108106443, T>A, chr6:30673359, T>G, chr19:8564523, T>G, chr9:137779251, G>A, chr19:7712287, G>C, chr16:81942175, A>G, chr6:32816772, C>A, chr6:32814942, C>T, chr1:92946625, G>C, chr22:23915583, T>C, chr22:35806756, G>A, chr2:163136505, C>G, chr1:27699670, AG>A and chr14:94847262, T>A.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr1:160769595, AG>A, chr6:51798908, C>T, chr21-45708278-G-A, chr1:196918605, A>G, chr6:3015818, G>A, chr22:23915745, G>A, chr19:8564523, T>G, chr6:30673359, T>G, chr9:137779251, G>A, chr19:7712287, G>C, chr11:67818269, G>A and chr16:81942175, A>G.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr19:48643270, C>T, chr22:35806756, G>A, chr1:92946625, G>C, chr2:163136505, C>G, chr22:23915583, T>C, chr11:108106443, T>A, chr6:32814942, C>T, chr6:32816772, C>A, chr1:27699670, AG>A, chr4:151793903, T>C and chr14:94847262, T>A.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr1:160769595, AG>A, chr6:51798908, C>T, chr21-45708278-G-A, chr1:196918605, A>G, chr6:3015818, G>A, chr22:23915745, G>A, chr19:8564523, T>G, chr6:30673359, T>G, chr9:137779251, G>A, chr19:7712287, G>C, chr11:67818269, G>A, chr16:81942175, A>G, chr19:48643270, C>T, chr22:35806756, G>A, chr1:92946625, G>C, chr2:163136505, C>G, chr22:23915583, T>C, chr11:108106443, T>A, chr6:32814942, C>T, chr6:32816772, C>A, chr1:27699670, AG>A, chr4:151793903, T>C and chr14:94847262, T>A.

In some embodiments, the one or more genetic variations do not comprise a genetic variation of chr2:163136505, C>G.

In some embodiments, the one or more genetic variations do not comprise a genetic variation of chr22:23915745, G>A.

In some embodiments, the one or more genetic variations do not comprise a genetic variation of chr16:81942175, A>G.

In some embodiments, the one or more genetic variations do not comprise a genetic variation of chr19:7712287, G>C.

In some embodiments, the one or more genetic variations do not comprise a genetic variation of chr11:67818269, G>A.

In some embodiments, the one or more genetic variations do not comprise a genetic variation of chr2:163136505, C>G; chr22:23915745, G>A; chr16:81942175, A>G; chr19:7712287, G>C; and chr11:67818269, G>A.

In some embodiments, the SNV is a heterozygous SNV.

In some embodiments, the SNV is a homozygous SNV.

In some embodiments, the one or more genetic variations comprise a pair of single nucleotide variations (SNVs), wherein the pair of SNVs are encoded by any one of SEQ ID NO pairs: 1003 and 1004, 1003 and 1005, 1006 and 1007, 1024 and 1025, 1030 and 1031, 1047 and 1048, 1049 and 1050, 1063 and 1064, 1063 and 1065, 1063 and 1066, 1075 and 1076, 1091 and 1093, 1091 and 1096, 1093 and 1095, 1094 and 1097, 1098 and 1099, 1098 and 1100, 1099 and 1100, 1102 and 1103, 1104 and 1106, 1104 and 1107, 1104 and 1108, 1104 and 1109, 1104 and 1110, 1104 and 1111, 1104 and 1112, 1110 and 1111, 1112 and 1113, 1119 and 1120, 1124 and 1125, 1124 and 1126, 1125 and 1126, 1140 and 1141, 1142 and 1144, 1146 and 1151, 1147 and 1148, 1147 and 1149, 1153 and 1146, 1153 and 1147, 1155 and 1156, 1160 and 1161, 1165 and 1166, 1186 and 1187, 1188 and 1193, 1189 and 1193, 1191 and 1192, 1191 and 1193, 1191 and 1195, 1192 and 1193, 1192 and 1195, 1196 and 1197, 1206 and 1207, 1210 and 1218, 1211 and 1213, 1212 and 1213, 1213 and 1215, 1213 and 1216, 1213 and 1217, 1233 and 1238, 1242 and 1243, 1245 and 1246, 1263 and 1260, 1269 and 1279, 1270 and 1279, 1270 and 1282, 1271 and 1279, 1274 and 1279, 1278 and 1279, 1278 and 1281, 1279 and 1280, 1279 and 1281, 1279 and 1282, 1292 and 1293, 1296 and 1297, 1305 and 1314, 1306 and 1310, 1313 and 1321 or 1315 and 1322 (see Table 9 or Tables 9 and 7 for a subset), or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a CNV with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to any one of SEQ ID NOs 157, 2, 140, 65, 26, 14 or 45 (see Tables 7 and 8), or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a CNV with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to any one of SEQ ID NOs 2, 140, 65, 26, 14 or 45 (see Table 7), or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a CNV with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to SEQ ID NO 157 (see Table 8), or a complement thereof.

In some embodiments, the one or more genetic variations comprise a CNV-SNV pair comprising a CNV and a single nucleotide variation (SNV), wherein the SNV of the CNV-SNV pair is encoded by any one of SEQ ID NO pairs: 146 and 1301, 85 and 1173, 58 and 1107, 58 and 1104, 91 and 1199, 103 and 1225, 103 and 1086 or 41 and 1223 (see Tables 1 and 10), or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of: chr8:145154222 G>A, chr2:163136505 C>G, chr16:81942175 A>G, chr8:61654298 T>A, and combinations thereof (see Tables 14 and 16).

In some embodiments, the one or more genetic variations disrupt or modulate one or more of the following genes: PLCG2, POLE, LRBA, EPG5 and SHARPIN (see Table 17).

In some embodiments, the one or more genetic variations disrupt or modulate one or more of the following genes: PLCG2, CHD7, IFIH1, AP3B1, EPG5, PIK3CD, LRBA and SHARPIN (see Table 18).

In some embodiments, the corresponding gene encodes a transcript with a sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to any one of SEQ ID NOs 173-455 or 1500-2177 (see Tables 4 and 12), 2204-2215, 2300-2893, or complements thereof.

In some embodiments, the corresponding gene encodes a transcript with a sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to any one of SEQ ID NOs 173-455 (see Table 4), or complements thereof.

In some embodiments, the corresponding gene encodes a transcript with a sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to any one of SEQ ID NOs 1500-2177 (see Table 12), or complements thereof.

In some embodiments, the corresponding gene encodes a transcript with a sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to any one of SEQ ID NOs 2204-2215, or complements thereof.

In some embodiments, the corresponding gene encodes a transcript with a sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to any one of SEQ ID NOs 2300-2893, or complements thereof.

In some embodiments, the one or more genetic variations comprise 2 or 3 or 4 or 5 or more genetic variations.

In some embodiments, the one or more genetic variations comprise 10 or more genetic variations.

In some embodiments, the one or more genetic variations comprise 20 or more genetic variations.

In some embodiments, the one or more genetic variations comprise 50 or more genetic variations.

In some embodiments, the genetic test or the testing comprises microarray analysis, PCR, sequencing, nucleic acid hybridization, or any combination thereof.

In some embodiments, the genetic test or the testing comprises microarray analysis selected from the group consisting of a Comparative Genomic Hybridization (CGH) array analysis and an SNP array analysis.

In some embodiments, the genetic test or the testing comprises sequencing, wherein the sequencing is selected from the group consisting of Massively Parallel Signature Sequencing (MPSS), polony sequencing, 454 pyrosequencing, Illumina sequencing, Illumina (Solexa) sequencing using 10× Genomics library preparation, SOLiD sequencing, ion semiconductor sequencing, DNA nanoball sequencing, heliscope single molecule sequencing, single molecule real time (SMRT) sequencing, RNAP sequencing, Nanopore DNA sequencing, sequencing by hybridization, and microfluidic Sanger sequencing.

In some embodiments, the genetic test or the testing comprises analyzing a whole genome of the subject.

In some embodiments, the genetic test or the testing comprises analyzing a whole exome of the subject.

In some embodiments, the genetic test or the testing comprises analyzing nucleic acid information that has already been obtained for a whole genome or a whole exome of the subject.

In some embodiments, the nucleic acid information is obtained from an in silico analysis.

In some embodiments, the subject is a human subject.

In some embodiments, the polynucleic acid sample comprises a polynucleic acid from blood, saliva, urine, serum, tears, skin, tissue, or hair of the subject.

In some embodiments, the method further comprises treating the subject with an agent that reduces a viral load in the subject.

In some embodiments, the immunosuppressive agent is administered after the viral load is reduced.

In some embodiments, the viral load is a JCV viral load.

In some embodiments, the agent that reduces the viral load is an agent that targets JCV.

In some embodiments, the method further comprises analyzing for a presence of JCV in a biological sample from the subject. In some embodiments, the method comprises a JCV-antibody test. In some embodiments, the JCV-antibody test has a negative result. In some embodiments, the JCV-antibody test does not detect a presence of JCV in the biological sample from the subject. In some embodiments, the JCV-antibody test detects a presence of JCV in the biological sample from the subject.

In some embodiments, the analyzing for a presence of JCV comprises contacting a JCV detection reagent to the biological sample.

In some embodiments, the JCV detection reagent is selected from the group consisting of an anti-JCV antibody, a JCV specific primer, and combinations thereof.

Provided herein is a method of treating a condition in a subject in need thereof, comprising: administering a therapeutically effective amount of one or more immunosuppressive medications to the subject, and one or more agents that reduce a viral load in the subject, wherein the subject is identified as not having a risk of developing progressive multifocal leukoencephalopathy (PML) by a genetic test. In some embodiments, the subject is identified as not having a high risk of developing progressive multifocal leukoencephalopathy (PML) by a genetic test.

Provided herein is a method of treating a condition in a subject in need thereof, comprising: analyzing a polynucleic acid sample from the subject for one or more genetic variations that disrupt or modulate a gene of GN1-GN765, wherein a genetic variation of the one or more genetic variations that disrupt or modulate a gene of GN1-GN765 is not present in the polynucleic acid sample; identifying the subject as not having a risk of developing PML; administering a therapeutically effective amount of one or more immunosuppressive medications to the subject. In some embodiments, the method comprises identifying the subject as not having a high risk of developing PML.

Provided herein is a method of identifying a subject as having a risk of developing PML, comprising: analyzing a polynucleic acid sample from the subject for one or more genetic variations that disrupt or modulate a gene of GN1-GN765, wherein a genetic variation of the one or more genetic variations that disrupt or modulate a gene of GN1-GN765 is not present in the polynucleic acid sample; identifying the subject as not having a risk of developing PML. In some embodiments, the method comprises identifying the subject as not having a high risk of developing PML.

Provided herein is a method of identifying a subject as having a risk of developing progressive multifocal leukoencephalopathy (PML) comprising obtaining a genetic test result from a polynucleic acid sample from a subject, and identifying the subject as having a risk of developing PML based on the genetic test result; wherein the subject is immunosuppressed.

Provided herein is a method of monitoring a subject as having a risk of developing progressive multifocal leukoencephalopathy (PML) comprising obtaining a genetic test result from a polynucleic acid sample from a subject, and identifying the subject as having an increased risk of developing PML based on the genetic test result; wherein the subject is immunosuppressed.

In some embodiments, the subject is on an immunosuppressive therapy.

Provided herein is a method of identifying a subject as having a risk of developing progressive multifocal leukoencephalopathy (PML) comprising detecting one or more genetic variations that disrupt or modulate a gene of GN1-GN765 in a polynucleic acid sample from a subject, and identifying the subject as having a risk of developing PML; wherein the subject is immunosuppressed.

Provided herein is a method of identifying a subject as having a risk of developing progressive multifocal leukoencephalopathy (PML) comprising: analyzing a polynucleic acid sample from the subject for one or more genetic variations that disrupt or modulate a gene of GN1-GN765, wherein a genetic variation of the one or more genetic variations that disrupt or modulate a gene of GN1-GN765 is present in the polynucleic acid sample; identifying the subject as having a risk of developing PML; wherein the subject is immunosuppressed. In some embodiments, the method comprises identifying the subject as having a high risk of developing PML.

In some embodiments, the method comprises not administering a therapeutically effective amount of one or more immunosuppressive medications to the subject identified as having a risk of developing PML.

In some embodiments, the method comprises analyzing for a presence of JCV in a biological sample from the subject. In some embodiments, the analyzing for a presence of JCV comprises a JCV-antibody test, a CD62L test, or a CSF IgM oligoclonal bands test. In some embodiments, the analyzing for a presence of JCV is performed prior to the genetic test. In some embodiments, the analyzing for a presence of JCV is performed after the genetic test. In some embodiments, the analyzing for a presence of JCV is performed concurrently with the genetic test. In some embodiments, the analyzing for a presence of JCV identifies the subject as having JCV. In some embodiments, the analyzing for a presence of JCV identifies the subject as not having JCV. In some embodiments, the genetic test result identifies the subject as having a risk or an increased risk of developing PML. In some embodiments, the genetic test result identifies the subject as not having a risk or not having an increased risk of developing PML.

In some embodiments, the subject is immunosuppressed. In some embodiments, the subject has HIV. In some embodiments, the subject has HIV infection. In some embodiments, the subject is at risk of HIV infection. In some embodiments, the method comprises administering a therapeutically effective amount of one or more antiviral drugs, such as protease inhibitors (lopinavir/ritonavir {e.g., KALETRA}, indinavir {e.g., CRIXIVAN}, ritonavir {e.g., NORVIR}, nelfinavir {e.g., VIRACEPT}, saquinavir hard gel capsules {e.g., INVIRASE}, atazanavir {e.g., REYATAZ}, amprenavir {e.g., AGENERASE}, fosamprenavir {e.g., TELZIR}, tipranavir{e.g., APTIVUS}), reverse transcriptase inhibitors, including non-nucleoside and nucleoside/nucleotide inhibitors (AZT {zidovudine, e.g., Retrovir}, ddI {didanosine, e.g., VIDEX}, 3TC {lamivudine, e.g., EPIVIR}, d4T {stavudine, e.g., ZERIT}, abacavir {e.g., ZIAGEN}, FTC {emtricitabine, e.g., EMTRIVA}, tenofovir {e.g., VIREAD}, efavirenz {e.g., SUSTIVA} and nevirapine {e.g., VIRAMUNE}), fusion inhibitors T20 {enfuvirtide, e.g., FUZEON}, integrase inhibitors (Raltegravir, e.g., ISENTRESS, MK-0518; and elvitegravir, e.g., VITEKTA, GS-9137), and maturation inhibitors (bevirimat {PA-457}).

In some embodiments, the condition is a cancer, a hematologic malignancy, an organ transplant, or an autoimmune disease. In some embodiments, the condition is idiopathic CD4+ lymphocytopenia (ICL).

In some embodiments, the condition is an autoimmune disease.

In some embodiments, the autoimmune disease is selected from the group consisting of Addison disease, Behcet's Disease, Inflammatory bowel disease, Celiac disease—sprue (gluten-sensitive enteropathy), Crohn's disease, Dermatomyositis, Focal segmental glomerulosclerosis, Graves disease, Hashimoto thyroiditis, Multiple sclerosis, Myasthenia gravis, Pemphigus, Pemphigoid, Aplastic anemia, Pernicious anemia, Autoimmune hemolytic anemia, Erythroblastopenia, Thrombocytopenic purpura, Evans syndrome, Vasculitis, Granulomatosis with polyangiitis, Chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome, Anti-NMDA receptor encephalitis, Devic's disease, Autoimmune pancreatitis, Opsoclonus myoclonus syndrome, IgG4-related disease, Psoriasis, Reactive arthritis, Rheumatoid arthritis, Juvenile idiopathic arthritis, Sarcoidosis, Sjögren syndrome, Systemic lupus erythematosus, Type I diabetes, Vitiligo, or Ulcerative colitis.

In some embodiments, the autoimmune disease is multiple sclerosis or Crohn's disease.

In some embodiments, the one or more immunosuppressive medications comprise a glucocorticoid, cytostatic, antibody, drug acting on immunophilins, interferon, opioid, TNF binding protein, mycophenolate, small biological agent, small molecule, organic compound, or any combination thereof.

In some embodiments, the one or more immunosuppressive medications comprise A2aR antagonist, Akt inhibitor, anti CD20, Anti-amyloidotic (AA) Agent, anti-CD37 protein therapeutic, anti-CTLA4 mAb, Anti-CXCR4, anti-huCD40 mAb, anti-LAG3 mAb, anti-PD-1 mAb, anti-PD-L1 agent, anti-PD-L1 agent, anti-PD-L1 mAb, anti-TGFb mAb, anti-TIGIT mAb, anti-TIM-3 mAb, Aurora kinase inhibitor, Bcl-2 Inhibitor, bifunctional fusion protein targeting TGFb and PD-L1, bispecific anti-PD-1 and anti-LAG3 mAb, CD1d ligand, CD40 agonist, Complement C5a inhibitor, CSF1R inhibitor, EZH2 inhibitor, FGFR3 inhibitor, FGFR4 inhibitor, FGFrR3 inhibitor, glucocorticoid-induced tumor necrosis factor receptor-related gene [GITR] agonist, glutaminase inhibitor, Human monoclonal antibody against IL-12, ICOS agonist, IDO1 inhibitor, IL2 mutein, IL2 receptor agonist, MEK inhibitor, multitargeted receptor tyrosine kinase inhibitor, neutrophil elastase inhibitor, Notch Inhibitor, p38 MAPK inhibitor, PD-1 inhibitor, recombinant human Flt3L, ROCK inhibitor, selective sphingosine-1-phosphate receptor modulator, Src kinase inhibitor, TLR4 agonist, TLR9 agonist, or any combination thereof.

In some embodiments, the one or more immunosuppressive medications comprise abatacept (e.g. ORENCIA), abrilumab, acalabrutinib, adalimumab, adrenocorticotropic hormone, agatolimod sodium, AJM300, aldesleukin, alefacept, alemtuzumab, alisertib, alvespimycin hydrochloride, alvocidib, ambrisentan (e.g. LETAIRIS), aminocamptothecin, amiselimod, anakinra, andecaliximab, andrographolides (a botanical medicinal herb also known as IB-MS), anifrolumab, antithymocyte Ig, apatinib, apelisib, asparaginase, atacicept, atezolizumab, avelumab, azacitidine, azathioprine, bafetinib, baminercept, baricitinib, basiliximab, becatecarin, begelomab, belatacept, belimumab, bemcentinib, bendamustine, bendamustine (e.g. bendamustine hydrochloride), betalutin with lilotomab, bevacizumab, BIIB033, BIIB059, BIIB061, bimekizumab, binimetinib, bleomycin, blinatumomab, BNZ-1, bortezomib (e.g. VELCADE), brentuximab vedotin, bryostatin 1, bucillamine, buparlisib, busulfan, canakinumab, capecitabine, carboplatin, carfilzomib, carmustine, cediranib maleate, cemiplimab, ceralifimod, cerdulatinib, certolizumab (e.g. certolizumab pegol), cetuximab, chidamide, chlorambucil, CHS-131, cilengitide, cirmtuzumab, cisplatin, cladribine, clazakizumab, clemastine, clioquinol, corticosteroids, cyclophosphamide, cyclosporine, cytarabine, cytotoxic chemotherapy, daclizumab, dalfampridine (e.g. AMPYRA), daprolizumab pegol, daratumumab, dasatinib, defactinib, defibrotide, denosumab, dexamethasone, diacerein, dimethyl fumarate, dinaciclib, diroximel fumarate (e.g. VUMERITY), doxorubicin, doxorubicin (e.g. doxorubicin hydrochloride), durvalumab, duvelisib, duvortuxizumab, eculizumab (e.g. SOLIRIS), efalizumab, eftilagimod alpha, EK-12 (a neuropeptide combination of metenkefalin and tridecactide), elezanumab, elotuzumab (e.g. EMPLICITI), encorafenib, enfuvirtida (e.g. FUZEON), entinostat, entospletinib, enzastaurin, epacadostat, epirubicin, epratuzumab, eritoran tetrasodium, etanercept, etoposide, etrolizumab, everolimus, evobrutinib, filgotinib, fingolimod (e.g. fingolimod hydrochloride), firategrast, fludarabine, fluorouracil, fontolizumab, forodesine hydrochloride, fostamatinib, galunisertib, ganetespib, ganitumab, gemcitabine, gemtuzumab ozogamicin, gerilimzumab, glasdegib, glassia, glatiramer acetate, glembatumumab vedotin, glesatinib, golimumab (e.g. SIMPONI), guadecitabine, hydrocortisone, hydroxychloroquine sulfate, hydroxyurea, ibritumomab tiuxetan, ibrutinib, ibudilast, idarubicin, idebenone, idelalisib, ifosfamide, iguratimod, imatinib, imexon, IMU-838, infliximab, inotuzumab ozogamicin, interferon alfa-2, interferon beta-1a, interferon beta-1b, interferon gamma-1, ipilimumab, irofulven, isatuximab, ispinesib, itacitinib, ixazomib, lapatinib, laquinimod, laromustine, ld-aminopterin, leflunomide, lenalidomide, lenvatinib, letrozole (e.g. FEMARA), levamisole, levocabastine, lipoic acid, lirilumab, lonafamib, lumiliximab, maraviroc (e.g. SELZENTRY), masitinib, mavrilimumab, melphalan, mercaptopurine, methotrexate, methoxsalen, methylprednisone, milatuzumab, mitoxantrone, mizoribine, mocetinostat, monalizumab, mosunetuzumab, motesanib diphosphate, moxetumomab pasudotox, muromonab-CD3, mycophenolate mofetil (e.g. mycophenolate mofetil hydrochloride), mycophenolic acid, namilumab, natalizumab, navitoclax, neihulizumab, nerispirdine, neurovax, niraparib, nivolumab, obatoclax mesylate, obinutuzumab, oblimersen sodium, ocrelizumab, ofatumumab, olokizumab, opicinumab, oprelvekin, osimertinib, otelixizumab, oxaliplatin, oxcarbazepine, ozanimod, paclitaxel, pacritinib, palifermin, panobinostat, pazopanib, peficitinib, pegfilgrastim (e.g. NEULASTA), peginterferon beta-1a, pegsunercept (peg stnf-ri), pembrolizumab, pemetrexed, penclomedine, pentostatin, perifosine, pevonedistat, pexidartinib, picoplatin, pidilizumab, pivanex, pixantrone, pleneva, plovamer acetate, polatuzumab vedotin, pomalidomide, ponatinib, ponesimod, prednisone/prednisolone, pyroxamide, R-411, ravulizimab-cwvz (e.g. (ULTOMIRIS), recombinant it-12, relatlimab, rhigf-1, rhigm22, rigosertib, rilonacept, ritonavir (e.g. NORVIR), rituximab, ruxolitinib, SAR442168/PRN2246, sarilumab, secukinumab, selumetinib, simvastatin, sintilimab, siplizumab, siponimod (e.g. MAYZENT), sirolimus (rapamycin), sirukumab, sitravatinib, sonidegib, sorafenib, sotrastaurin acetate, sunitinib, sunphenon epigallocatechin-gallate, tabalumab, tacrolimus (e.g. tacrolimus anhydrous), talabostat mesylate, talacotuzumab, tanespimycin, tegafur/gimeracil/oteracil, temozolomide, temsirolimus, tenalisib, terameprocol, teriflunomide, thalidomide, thiarabine, thiotepa, tipifarnib, tirabrutinib, tislelizumab, tivozanib, tocilizumab, tofacitinib, TR-14035, tregalizumab, tremelimumab, treosulfan, ublituximab, umbralisib, upadacitinib, urelumab, ustekinumab, varlilumab, vatelizumab, vedolizumab, veliparib, veltuzumab, venetoclax, vinblastine, vincristine, vinorelbine ditartrate, visilizumab, vismodegib, vistusertib, voriconazole (e.g. VFEND), vorinostat, vosaroxin, ziv-aflibercept, or any combination thereof.

In some embodiments, the one or more immunosuppressive medications comprise 2B3-201, 3PRGD2, 4SC-202, 506U78, 6,8-bis(benzylthio)octanoic acid, 68Ga-BNOTA-PRGD2, 852A, 89Zr-DFO-CZP, ABBV-257, ABL001, ABP 501, ABP 710, ABP 798, ABT-122, ABT-199, ABT-263, ABT-348, ABT-494, ABT-555, ABT-874, ABX-1431 HCl, ACP-196, ACP-319, ACT-128800, ACY-1215, AD 452, Ad-P53, ADCT-301, ADCT-402, ADL5859, ADS-5102, AFX-2, AGEN1884, AGEN2034, AGS67E, AIN457, AK106-001616, ALD518, ALKS 8700, ALT-803, ALT-803, ALX-0061, ALXN1007, ALXN6000, AMD3100, AMG 108, AMG 319, AMG 357, AMG 570, AMG 592, AMG 714, AMG 719, AMG 827, AMP-110, AP1903, APL A12, AP0866, APX005M, AQ4N, AR-42, ARN-6039, ARQ 531, ARRY-371797, ARRY-382, ARRY-438162, ART-I02, ART621, ASK8007, ASNO02, ASP015K, ASP1707, ASP2408, ASP2409, ASP5094, AT-101, AT7519M, AT9283, ATA188, ATN-103, ATX-MS-1467, AVL-292, AVP-923, AZD4573, AZD5672, AZD5991, AZD6244, AZD6738, AZD9056, AZD9150, AZD9567, AZD9668, B-701, BAF312, BAY1830839, BBI608, BCD-054, BCD-055, BCD-063, BCD-089, BCD-100, BCD-132, BCD-145, BEZ235, BG00012, BG9924, BGB-3111, BGB-A333, BGG492, BHT-3009, BI 655064, BI 695500, BI 695501, BI 836826, BI-1206, MBR 796 BS, BIIB017, BIIB023, BIIB057, BIIB061, BIIL 284 BS, BLZ945, BMMNC, BMN 673, BMS-247550, BMS-582949, BMS-817399, BMS-936558, BMS-936564, BMS-945429, BMS-986104, BMS-986142, BMS-986156, BMS-986195, BMS-986205, BMS-986213, BMS-986226, BMS-986251, BNC105P, BOW015, BP1001, BT061, BTT-1023, C105, CAL-101, CAM-3001, CAT-8015, CB-839, CBL0137, CC-1088, CC-115, CC-122, CC-292, CC100, CCI-779, CCX 354-C, CDKI AT7519, CDP323, CDP6038, CDP870, CDX-1127, CDX-301, CE-224535, CF101, CFZ533, CGP 77116, CH-1504, CH-4051, CHR-5154, CHS-0214, CK-2017357, CLAG-M, CLR 131, CMAB008, CMP-001, CNF2024 (BIIB021), CNM-Au8, CNTO 1275, CNTO 136, CNTO 148, CNTO 6785, CP-195543, CP-461, CpG 7909, CPI-1205, CR6086, CRx-102, CS-0777, CS1002, CT-011, CT-1530, CT-P10, CV301, CX-3543, DAC-HYP, DCDT2980S, DI-B4, DPA-714 FDG, DS-3032b, DT2219ARL, DTRM-505, DTRM-555, DTRMWXHS-12, DWP422, E6011, E7449, EK-12, ELND002, ENIA11, EOC202, ETBX-011, F81L10, FBTA05, FEDAA1106 (BAY85-8101), FGF401, FKB327, FPA008, FR104, FS118, FTY720, G100, GCS-100, GDC-0199, GDC-0853, GEH120714, GLPG0259, GLPG0634, GNbAC1, GNKG168, GP2013, GP2015, GRN163L, GS-1101, GS-5745, GS-9219, GS-9820, GS-9876, GS-9901, GSK1223249, GSK1827771, GSK2018682, GSK21110183, GSK239512, GSK2618960, GSK2831781, GSK2982772, GSK3117391, GSK3152314A, GSK3196165, GSK3358699, GSK706769, GW-1000-02, GW274150, GW406381, GW856553, GZ402668, HCD122, HE3286, HL2351, HL237, hLL1-DOX (IMMU-115), HLX01, HM71224, HMPL-523, HSC835, HZT-501, ICP-022, IDEC-C2B8, ILV-094, IMGN529, IMMU-114, IMO-2125, INCAGN02385, INCB018424, INCB028050, INCB039110, INCB047986, INCMGA00012, INNO-406, INT131, INT230-6, INVAC-1, IPI-145, IPX056, ISF35, ISIS 104838, ITF2357, JCARH125, JHL1101, JNJ 38518168, JNJ-39758979, JNJ-40346527, JNJ-63723283, JS001, JTE-051, JTX-2011, KB003, KD025, KPT-330, KW-2449, KW-2478, KX2-391, L-778123, LAG525, LAM-002A, LBEC0101, LBH589, LFB-R603, LMB-2, LX3305, LY2127399, LY2189102, LY2439821, LY3009104, LY3090106, LY3300054, LY3321367, LY3337641, M2951, M7824, M923, MBG453, MBP8298, MBS2320, MD1003, MDG013, MDV9300, MDX-1100, MDX-1342, MDX-1411, ME-401, MEDI-522, MEDI-538, MEDI-551, MEDI4920, MGA012, MGCD0103, MGD007, MIS416, MK-0873, MK-4280, MK-4827, MK-8457, MK-8808, MK0359, MK0457, MK0752, MK0782, MK0812, MK2206, MLN1202, MLTA3698A, MM-093, MN-122, MN-166, monoclonal antibody M-T412, monoclonal antibody mono-dgA-RFB4, MOR00208, MOR103, MORAb-022, MP-435, MP470, MRC375, MRG-106, MS-533, MSB11022, MSC2490484A, MT-1303, MT-3724, MTIG7192A, MTRX1011A, NBI-5788, NC-503, NI-0101, NI-071, NIS793, NKTR-214, NNC 0141-0000-0100, NNC 0151-0000-0000, NNC0109-0012, NNC0114-0000-0005, NNC0114-0006, NNC0142-0002, NNCO215-0384, NNC109-0012, NOX-A12, NT-KO-003, NU100, OMB157, OMP-313M32, ON01910 Na, ONO-2506P0, ONO-4641, ONTAK, OPB 31121, OSI-461, OTS167IV, P1446A-05, PBF-509, PBRO6, PCI 32765, PCI-24781, PD 0360324, PDA001, PDR001, PF-04171327, PF-04236921, PF-04308515, PF-04629991, PF-05280586, PF-06342674, PF-06410293, PF-06438179, PF-06650833, PF-06651600, PF-06835375, PG-760564, PH-797804, PLA-695, PLX3397, PLX5622, POL6326, PRO131921, PRO283698, PRTX-100, PS-341, PTL201, R(+)XK469, R788, RAD001, RC18, REGN1979, REGN3767, REGN2810, REGN4659, RFT5-SMPT-dgA, RG2077, RGB-03, RGI-2001, RHB-104, RNS60, RO5045337, RO7123520, Rob 803, RPC1063, RWJ-445380, S 55746, SAIT101, SAN-300, SAR245409, SB-681323, SB683699, SBI-087, SC12267 (4SC-101), SCH 727965, SCIO-469, SD-101, SG2000, SGN-40, SHC014748M, SHR-1210, SHR0302, SHR1020, SJG-136, SKI-O-703, SMP-114, SNS-032, SNS-062, SNX-5422, SPARC1103 I, SPC2996, SSR150106, STA 5326 mesylate, Sunpharma1505, SyB L-0501, Sym022, Sym023, SYN060, T-614, T0001, TA-650, TAB08, TAK-715, TAK-783, TAK-901, TGR-1202, TH-302, TL011, TMI-005, TMP001, TNFa Kinoid, TP-0903, TRU-015, TRU-016, TSR-022, TSR-033, TSR-042, TXA127, VAY736, VP-16, VSN16R, VX-509, VX-702, VX-745, VX15/2503, XCEL-MC-ALPHA, XL228, XL844, XmAb13676, XmAb5574, XOMA 052, YRA-1909, Z102, ZEN003365, or any combination thereof.

In some embodiments, the one or more immunosuppressive medications comprise interferon beta-1a, interferon beta-1b, glatiramer acetate, peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone, rituximab, natalizumab, daclizumab, ocrelizumab, diroximel fumarate, siponimod or any combination thereof

In some embodiments, the one or more immunosuppressive medications comprise natalizumab (e.g., TYSABRI).

In some embodiments, the one or more genetic variations comprise a point mutation, polymorphism, single nucleotide polymorphisms (SNP), single nucleotide variation (SNV), translocation, insertion, deletion, amplification, inversion, interstitial deletion, copy number variation (CNV), structural variation (SV), loss of heterozygoity, or any combination thereof.

In some embodiments, the one or more genetic variations result in a loss of function of the corresponding gene.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of gene numbers (GNs) GN1-GN490.

In some embodiments, the gene comprises a gene selected from the group consisting of gene numbers (GNs) 1-156 (in Table 3).

In some embodiments, the gene comprises a gene selected from the group consisting of gene numbers (GNs) in Table 6.

In some embodiments, the gene comprises a gene selected from the group consisting of gene numbers (GNs) GN491-GN492 in Table 29.

In some embodiments, the gene comprises a gene selected from the group consisting of gene numbers (GNs) GN493-GN762 in Table 31.

In some embodiments, the gene comprises a gene selected from the group consisting of gene numbers (GNs) GN763-GN765 in Table 48.

In some embodiments, the corresponding gene comprises a gene selected from Tables 34-40, 42, 45A, 45B, 45C, 48, 50A, 50B and 51-62.

In some embodiments, the gene comprises a gene selected from the group consisting of PLCG2, RBCK1, EPG5, IL17F, SHARPIN, PRF1, JAGN1, TAP1, POLE, LRBA, EHF, IL12B, ATL2, NHEJ1, LYST, HIVEP1, AP3B1, TNFRSF10A, PIK3CD, PNP, MCEE, DOCK2 and ALG12 (see Table 13).

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of PLCG2, RBCK1, EPG5, IL17F, SHARPIN, PRF1, JAGN1, TAP1, POLE, LRBA, EHF, IL12B, ATL2, NHEJ1, LYST, HIVEP1, AP3B1, TNFRSF10A, PIK3CD, PNP, MCEE, DOCK2, ALG12, FCN2, LY9 and PRAM1.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of FCN2, LY9 and PRAM1.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of AIRE, ATM, C8B, CFHR2, DNASE1L3, DNER, FCN2, FCN3, GFI1, HIVEP3, IFIH1, IGLL1, LIG1, LRBA, LY9, MCM5, MDC1, NQO2, PKHD1, PLCG2, PRAM1, SERPINA1, STXBP2, TAP1 and TCIRG1.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of AIRE, ATM, C8B, CFHR2, DNASE1L3, DNER, FCN2, FCN3, GFI1, HIVEP3, IGLL1, LIG1, LRBA, LY9, MCM5, MDC1, NQO2, PKHD1, PRAM1, SERPINA1, and TAN.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of IGLL1, MDC1, STXBP2, FCN2, IGLL1, MCM5 and IFIH1.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of PRAM1, ATM, TAP1, PLCG2, FCN3, DNER, SERPINA1 and LRBA.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of IGLL1, MDC1, STXBP2, PRAM1, ATM, FCN2, IGLL1, MCM5, IFIH1, TAP1, PLCG2, FCN3, DNER, SERPINA1 and LRBA.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of LY9, LIG1, PKHD1, AIRE, GFI1, CFHR2, NQO2, C8B, DNASE1L3 and PLCG2.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of PRAM1, HIVEP3 and TCIRG1.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of LY9, LIG1, PKHD1, AIRE, GFI1, CFHR2, NQO2, PRAM1, C8B, DNASE1L3, PLCG2, HIVEP3 and TCIRG1.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of PKHD1, LY9, CFHR2, NQO2, AIRE, IGLL1, TCIRG1, ATM, MDC1, PRAM1, FCN2, STXBP2 and PLCG2.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of TAP1, GFI1, IGLL1, MCM5, IFIH1, FCN3, SERPINA1.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of PKHD1, LY9, CFHR2, NQO2, AIRE, TCIRG1, ATM, MDC1, PRAM1, FCN2, STXBP2, PLCG2, TAP1, GFI1, IGLL1, MCM5, IFIH1, FCN3 and SERPINA1.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of LY9, PKHD1, AIRE, CFHR2, NQO2, IGLL1, PRAM1, MDC1, FCN2, STXBP2, TCIRG1 and PLCG2.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of LIG1, MCM5, GFI1, IFIH1, IGLL1, ATM, TAP1, FCN3, LRBA and SERPINA1.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to SEQ ID NOs 1-172 or SRN1-SRN363, with 100% sequence identity to SEQ ID NOs 1000-1329, or with at least 80% and less than 100% sequence identity to GN1-GN490, or complements thereof.

In some embodiments, the one or more genetic variations are encoded by a sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to SEQ ID NOs 2200-2203, or SRN364-SRN366, with 100% sequence identity to SEQ ID NOs 3000-3274, or with at least 80% and less than 100% sequence identity to GN491-GN765, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a CNV with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to SEQ ID NOs 1-172, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a CNV with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to SEQ ID NOs 2200-2203, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a CNV sub-region (SRN) with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to SRN1-SRN363, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a CNV sub-region (SRN) with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to SRN364-SRN366, or complements thereof.

In some embodiments, the one or more genetic variations are encoded by a single nucleotide variation (SNV) with a sequence of any one of SEQ ID NOs: 1000-1329, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a single nucleotide variation (SNV) with a sequence of any one of SEQ ID NOs: 3000-3274, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a sequence with at least 80% and less than 100% sequence identity to GN1-GN490, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a sequence with at least 80% and less than 100% sequence identity to GN491-GN765, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a single nucleotide variation (SNV) with a sequence of any one of SEQ ID NO: 1000, 1001, 1002, 1009, 1010, 1011, 1012, 1014, 1016, 1017, 1019, 1020, 1028, 1032, 1033, 1034, 1035, 1036, 1037, 1040, 1041, 1043, 1051, 1054, 1056, 1057, 1058, 1059, 1061, 1062, 1063, 1066, 1068, 1069, 1070, 1071, 1073, 1074, 1075, 1076, 1077, 1078, 1080, 1082, 1084, 1090, 1092, 1098, 1099, 1100, 1101, 1104, 1107, 1114, 1116, 1118, 1121, 1122, 1123, 1125, 1126, 1127, 1128, 1129, 1130, 1131, 1133, 1135, 1136, 1137, 1138, 1142, 1146, 1147, 1148, 1150, 1152, 1154, 1157, 1160, 1161, 1165, 1166, 1167, 1168, 1169, 1171, 1174, 1175, 1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1193, 1194, 1200, 1201, 1202, 1203, 1204, 1208, 1219, 1220, 1221, 1222, 1226, 1227, 1228, 1229, 1230, 1231, 1232, 1235, 1239, 1247, 1248, 1249, 1250, 1251, 1252, 1254, 1255, 1256, 1259, 1260, 1261, 1263, 1264, 1266, 1267, 1273, 1278, 1279, 1283, 1284, 1286, 1287, 1289, 1290, 1291, 1299, 1300, 1301, 1304, 1311, 1327 or 1328 (see Tables 7 and 8), or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a single nucleotide variation (SNV) with a sequence of any one of SEQ ID NO: 1011, 1020, 1028, 1032, 1034, 1035, 1036, 1040, 1056, 1069, 1073, 1077, 1101, 1114, 1123, 1125, 1126, 1127, 1135, 1142, 1146, 1147, 1148, 1152, 1154, 1157, 1167, 1174, 1184, 1193, 1194, 1203, 1208, 1221, 1222, 1229, 1235, 1252, 1255, 1256, 1259, 1260, 1261, 1263, 1273, 1278, 1279, 1284, 1287, 1289, 1299 or 1311 (see Table 7), or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a single nucleotide variation (SNV) with a sequence of any one of SEQ ID NO: 1000, 1001, 1002, 1009, 1010, 1012, 1014, 1016, 1017, 1019, 1033, 1037, 1041, 1043, 1051, 1054, 1057, 1058, 1059, 1061, 1062, 1063, 1066, 1068, 1070, 1071, 1074, 1075, 1076, 1078, 1080, 1082, 1084, 1090, 1092, 1098, 1099, 1100, 1104, 1107, 1116, 1118, 1121, 1122, 1128, 1129, 1130, 1131, 1133, 1136, 1137, 1138, 1146, 1147, 1150, 1152, 1160, 1161, 1165, 1166, 1168, 1169, 1171, 1175, 1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1200, 1201, 1202, 1204, 1219, 1220, 1226, 1227, 1228, 1230, 1231, 1232, 1239, 1247, 1248, 1249, 1250, 1251, 1252, 1254, 1264, 1266, 1267, 1278, 1279, 1283, 1286, 1290, 1291, 1300, 1301, 1304, 1327 or 1328 (see Table 8), or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a single nucleotide variation (SNV) with a sequence of any one of SEQ ID NO: 3300-3351, 3400-3467 or 3500-3526.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr16:81942175 A>G, chr2:163136505 C>G, chr11:67818269 G>A, chr22:23917192 G>T, chr20:3846397 C>T, chr8:145154222, G>A chr8:61654298 T>A, chr3:39323163 A>C, chr4:151199080 G>A, chr1:42047208 C>G, chr2:163124051 C>T, chr1:182554557 C>T, chr8:145154824 A>C, chr20:62305450 C>T, chr22:23915745 G>A, chr6:83884161 C>G, chr11:108202772 G>T, chr5:138856923 C>T, chr16:1510535 C>T, chr20:3843027 C>A, chr12:122064788 G>GT, chr16:7714909 C>T, chr18:56401523 C>T, chr1:92946625 G>C, chr5:169081453 G>C, chr11:108117787 C>T, chr22:21235389 A>G, chr19:4817657 C>T, chr10:1060218 G>A, chr21:30698953 T>G, chr9:304628 G>A, chr19:7712287 G>C, chr10:90771767 G>A, chr3:121415370 T>C, chr16:70503095 A>G, chr1:206945738 C>T, chr5:156593120 C>T, chr4:27019452 C>T, chr1:155317682 C>T, chr17:77926526 C>T, chr1:235840495 G>T, chr14:21993359 G>A, chr8:61757805 C>T, chr15:91306241 G>A, chr16:50741791 C>T, chr22:23915583 T>C, chr2:47205921 C>T, chr12:88900891 C>A, chr3:142281353 C>G, chr11:108123551 C>T, chr1:207641950 C>T, chr6:143092151 T>C, chr2:24431184 C>T, chr2:24432937 C>T, chr9:312134 G>A, chr8:100205255 G>A, chr21:16339852 T>C, and any combination thereof (see Tables 14 and 15).

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr16:81942175 A>G, chr2:163136505 C>G, chr11:67818269 G>A, chr22:23917192 G>T, chr20:3846397 C>T, chr8:145154222, G>A chr8:61654298 T>A, chr3:39323163 A>C, chr4:151199080 G>A, chr1:42047208 C>G, chr2:163124051 C>T, chr1:182554557 C>T, and any combination thereof (see Table 14).

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr8:145154824 A>C, chr20:62305450 C>T, chr22:23915745 G>A, chr6:83884161 C>G, chr11:108202772 G>T, chr5:138856923 C>T, chr16:1510535 C>T, chr20:3843027 C>A, chr12:122064788 G>GT, chr16:7714909 C>T, chr18:56401523 C>T, chr1:92946625 G>C, chr5:169081453 G>C, chr11:108117787 C>T, chr22:21235389 A>G, chr19:4817657 C>T, chr10:1060218 G>A, chr21:30698953 T>G, chr9:304628 G>A, chr19:7712287 G>C, chr10:90771767 G>A, chr3:121415370 T>C, chr16:70503095 A>G, chr1:206945738 C>T, chr5:156593120 C>T, chr4:27019452 C>T, chr1:155317682 C>T, chr17:77926526 C>T, chr1:235840495 G>T, chr14:21993359 G>A, chr8:61757805 C>T, chr15:91306241 G>A, chr16:50741791 C>T, chr22:23915583 T>C, chr2:47205921 C>T, chr12:88900891 C>A, chr3:142281353 C>G, chr11:108123551 C>T, chr1:207641950 C>T, chr6:143092151 T>C, chr2:24431184 C>T, chr2:24432937 C>T, chr9:312134 G>A, chr8:100205255 G>A, chr21:16339852 T>C, and any combination thereof (see Table 15).

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr1:196759282, C>T, chr4:126412634, C>G, chr10:75673748, A>C, chr6:30675830, T>A, chr6:30680721, G>A, chr12:56385915, GGGA>G, chr18:57103126, G>A, chr3:171321023, C>T, chr1:59131311, G>T, chr22:31008867, T>C, chr2:74690378, C>T, chr17:7592168, C>G, chr2:74690039, G>A, chr12:113448288, A>G, chr17:76130947, G>T, chr2:15674686, T>C, chr2:15607842, T>C, chr14:94847262, T>A, chr4:126412154, G>A, chr22:37271882, T>C, chr20:44640959, G>A, chr17:8138569, C>G, chr12:113357237, G>C, chr12:113357209, G>A, chr11:60893235, C>T, chr12:113357442, G>A, chr5:40964852, A>C, chr14:35497285, T>C, chr19:55494157, G>A, and any combination thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr11:72145307, C>G, chr7:30491421, G>T, chr6:30673403, A>G, chr19:44153248, T>C, chr17:43555253, A>G, chr2:188349523, A>G, chr1:57409459, C>A, chr4:126241248, C>G, chr5:39311336, A>T, chr17:76129619, C>T, chr4:110929301, T>C, chr3:11402163, G>A, chr16:67694044, C>T, chr19:10395141, G>A, chr6:106740989, T>C, chr1:183532364, T>A, chr22:35806756, G>A, chr4:110865044, G>C, chr4:110864533, C>T, chr4:126238090, G>T, chr4:110932508, C>A, chr6:31605016, T>C, chr7:92733766, C>A, chr18:29645930, A>T, and any combination thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr21:45708278, G>A, chr11:108106443, T>A, chr1:57409459, C>A, chr1:196918605, A>G, chr3:58191230, G>T, chr2:230579019, G>A, chr9:137779251, G>A, chr1:27699670, AG>A, chr1:92946625, G>C, chr1:42047208, C>G, chr2:163136505, C>G, chr22:23915583, T>C, chr22:23915745, G>A, chr19:48643270, C>T, chr4:151793903, T>C, chr1:160769595, AG>A, chr22:35806756, G>A, chr6:30673359, T>G, chr6:3015818, G>A, chr6:51798908, C>T, chr16:81942175, A>G, chr19:8564523, T>G, chr14:94847262, T>A, chr19:7712287, G>C, chr6:32814942, C>T, chr6:32816772, C>A and chr11:67818269, G>A.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr22:23915745, G>A, chr6:30673359, T>G, chr19:7712287, G>C, chr9:137779251, G>A, chr22:23915583, T>C, chr22:35806756, G>A and chr2:163136505, C>G. In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr19:8564523, T>G, chr11:108106443, T>A, chr6:32816772, C>A, chr6:32814942, C>T, chr16:81942175, A>G, chr1:27699670, AG>A, chr2:230579019, G>A, chr14:94847262, T>A and chr4:151793903, T>C.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr22:23915745, G>A, chr6:30673359, T>G, chr19:7712287, G>C, chr19:8564523, T>G, chr11:108106443, T>A, chr9:137779251, G>A, chr22:23915583, T>C, chr22:35806756, G>A, chr2:163136505, C>G, chr6:32816772, C>A, chr6:32814942, C>T, chr16:81942175, A>G, chr1:27699670, AG>A, chr2:230579019, G>A, chr14:94847262 and T>A, chr4:151793903, T>C.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr1:160769595, AG>A, chr19:48643270, C>T, chr6:51798908, C>T, chr21-45708278-G-A, chr1:92946625, G>C, chr1:196918605, A>G, chr6:3015818, G>A, chr1:57409459, C>A, chr3:58191230, G>T and chr16:81942175, A>G.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr19:8564523, T>G, chr1:42047208, C>G and chr11:67818269, G>A

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr1:160769595, AG>A, chr19:48643270, C>T, chr6:51798908, C>T, chr21-45708278-G-A, chr1:92946625, G>C, chr1:196918605, A>G, chr6:3015818, G>A, chr19:8564523, T>G, chr1:57409459, C>A, chr3:58191230, G>T, chr16:81942175, A>G, chr1:42047208, C>G and chr11:67818269, G>A.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr6:51798908, C>T, chr1:160769595, AG>A, chr1:196918605, A>G, chr6:3015818, G>A, chr21-45708278-G-A, chr22:23915745, G>A, chr11:67818269, G>A, chr11:108106443, T>A, chr6:30673359, T>G, chr19:8564523, T>G, chr9:137779251, G>A, chr19:7712287, G>C and chr16:81942175, A>G.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr6:32816772, C>A, chr6:32814942, C>T, chr1:92946625, G>C, chr22:23915583, T>C, chr22:35806756, G>A, chr2:163136505, C>G, chr1:27699670, AG>A and chr14:94847262, T>A.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr6:51798908, C>T, chr1:160769595, AG>A, chr1:196918605, A>G, chr6:3015818, G>A, chr21-45708278-G-A, chr22:23915745, G>A, chr11:67818269, G>A, chr11:108106443, T>A, chr6:30673359, T>G, chr19:8564523, T>G, chr9:137779251, G>A, chr19:7712287, G>C, chr16:81942175, A>G, chr6:32816772, C>A, chr6:32814942, C>T, chr1:92946625, G>C, chr22:23915583, T>C, chr22:35806756, G>A, chr2:163136505, C>G, chr1:27699670, AG>A and chr14:94847262, T>A.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr1:160769595, AG>A, chr6:51798908, C>T, chr21-45708278-G-A, chr1:196918605, A>G, chr6:3015818, G>A, chr22:23915745, G>A, chr19:8564523, T>G, chr6:30673359, T>G, chr9:137779251, G>A, chr19:7712287, G>C, chr11:67818269, G>A and chr16:81942175, A>G.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr19:48643270, C>T, chr22:35806756, G>A, chr1:92946625, G>C, chr2:163136505, C>G, chr22:23915583, T>C, chr11:108106443, T>A, chr6:32814942, C>T, chr6:32816772, C>A, chr1:27699670, AG>A, chr4:151793903, T>C and chr14:94847262, T>A.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr1:160769595, AG>A, chr6:51798908, C>T, chr21-45708278-G-A, chr1:196918605, A>G, chr6:3015818, G>A, chr22:23915745, G>A, chr19:8564523, T>G, chr6:30673359, T>G, chr9:137779251, G>A, chr19:7712287, G>C, chr11:67818269, G>A, chr16:81942175, A>G, chr19:48643270, C>T, chr22:35806756, G>A, chr1:92946625, G>C, chr2:163136505, C>G, chr22:23915583, T>C, chr11:108106443, T>A, chr6:32814942, C>T, chr6:32816772, C>A, chr1:27699670, AG>A, chr4:151793903, T>C and chr14:94847262, T>A.

In some embodiments, the one or more genetic variations do not comprise a genetic variation of chr2:163136505, C>G.

In some embodiments, the one or more genetic variations do not comprise a genetic variation of chr22:23915745, G>A.

In some embodiments, the one or more genetic variations do not comprise a genetic variation of chr16:81942175, A>G.

In some embodiments, the one or more genetic variations do not comprise a genetic variation of chr19:7712287, G>C.

In some embodiments, the one or more genetic variations do not comprise a genetic variation of chr11:67818269, G>A.

In some embodiments, the one or more genetic variations do not comprise a genetic variation of chr2:163136505, C>G; chr22:23915745, G>A; chr16:81942175, A>G; chr19:7712287, G>C; and chr11:67818269, G>A.

In some embodiments, the SNV is a heterozygous SNV.

In some embodiments, the SNV is a homozygous SNV.

In some embodiments, the one or more genetic variations comprise a pair of single nucleotide variations (SNVs), wherein the pair of SNVs are encoded by any one of SEQ ID NO pairs: 1003 and 1004, 1003 and 1005, 1006 and 1007, 1024 and 1025, 1030 and 1031, 1047 and 1048, 1049 and 1050, 1063 and 1064, 1063 and 1065, 1063 and 1066, 1075 and 1076, 1091 and 1093, 1091 and 1096, 1093 and 1095, 1094 and 1097, 1098 and 1099, 1098 and 1100, 1099 and 1100, 1102 and 1103, 1104 and 1106, 1104 and 1107, 1104 and 1108, 1104 and 1109, 1104 and 1110, 1104 and 1111, 1104 and 1112, 1110 and 1111, 1112 and 1113, 1119 and 1120, 1124 and 1125, 1124 and 1126, 1125 and 1126, 1140 and 1141, 1142 and 1144, 1146 and 1151, 1147 and 1148, 1147 and 1149, 1153 and 1146, 1153 and 1147, 1155 and 1156, 1160 and 1161, 1165 and 1166, 1186 and 1187, 1188 and 1193, 1189 and 1193, 1191 and 1192, 1191 and 1193, 1191 and 1195, 1192 and 1193, 1192 and 1195, 1196 and 1197, 1206 and 1207, 1210 and 1218, 1211 and 1213, 1212 and 1213, 1213 and 1215, 1213 and 1216, 1213 and 1217, 1233 and 1238, 1242 and 1243, 1245 and 1246, 1263 and 1260, 1269 and 1279, 1270 and 1279, 1270 and 1282, 1271 and 1279, 1274 and 1279, 1278 and 1279, 1278 and 1281, 1279 and 1280, 1279 and 1281, 1279 and 1282, 1292 and 1293, 1296 and 1297, 1305 and 1314, 1306 and 1310, 1313 and 1321 or 1315 and 1322 (see Table 9 or Tables 9 and 7 for a subset), or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a CNV with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to any one of SEQ ID NOs 157, 2, 140, 65, 26, 14 or 45 (see Tables 7 and 8), or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a CNV with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to any one of SEQ ID NOs 2, 140, 65, 26, 14 or 45 (see Table 7), or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a CNV with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to SEQ ID NO 157 (see Table 8), or a complement thereof.

In some embodiments, the one or more genetic variations comprise a CNV-SNV pair comprising a CNV and a single nucleotide variation (SNV), wherein the SNV of the CNV-SNV pair is encoded by any one of SEQ ID NOs 1301, 1173, 1107, 1104, 1199, 1225, 1086 or 1223 (see Table 10), or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of one or more of the following: chr8:145154222 G>A, chr2:163136505 C>G, chr16:81942175 A>G, and chr8:61654298 T>A (see Tables 14 and 16).

In some embodiments, the one or more genetic variations disrupt or modulate one or more of the following genes: PLCG2, POLE, LRBA, EPG5 and SHARPIN (see Table 17).

In some embodiments, the one or more genetic variations disrupt or modulate one or more of the following genes: PLCG2, CHD7, IFIH1, AP3B1, EPG5, PIK3CD, LRBA and SHARPIN (see Table 18).

In some embodiments, the gene encodes a transcript with a sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to any one of SEQ ID NOs 173-455 or 1500-2177 (see Tables 4 and 12), or complements thereof.

In some embodiments, the gene encodes a transcript with a sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to any one of SEQ ID NOs 173-455 (see Table 4), or complements thereof.

In some embodiments, the gene encodes a transcript with a sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to any one of SEQ ID NOs 1500-2177 (see Table 12), or complements thereof.

In some embodiments, the one or more genetic variations comprise 2 or 3 or 4 or 5 or more genetic variations.

In some embodiments, the one or more genetic variations comprise 10 or more genetic variations.

In some embodiments, the one or more genetic variations comprise 20 or more genetic variations.

In some embodiments, the one or more genetic variations comprise 50 or more genetic variations.

In some embodiments, the analyzing comprises microarray analysis, PCR, sequencing, nucleic acid hybridization, or any combination thereof.

In some embodiments, the genetic test result comprises a genetic test result from a microarray analysis, PCR, sequencing, nucleic acid hybridization, or any combination thereof.

In some embodiments, the detecting comprises a microarray analysis, PCR, sequencing, nucleic acid hybridization, or any combination thereof.

In some embodiments, the microarray analysis selected from the group consisting of a Comparative Genomic Hybridization (CGH) array analysis and an SNP array analysis.

In some embodiments, the sequencing is selected from the group consisting of Massively Parallel Signature Sequencing (MPSS), polony sequencing, 454 pyrosequencing, Illumina sequencing, Illumina (Solexa) sequencing using 10× Genomics library preparation, SOLiD sequencing, ion semiconductor sequencing, DNA nanoball sequencing, heliscope single molecule sequencing, single molecule real time (SMRT) sequencing, RNAP sequencing, Nanopore DNA sequencing, sequencing by hybridization, and microfluidic Sanger sequencing.

In some embodiments, the analyzing comprises analyzing a whole genome of the subject.

In some embodiments, the analyzing comprises analyzing a whole exome of the subject.

In some embodiments, the analyzing comprises analyzing nucleic acid information that has already been obtained for a whole genome or a whole exome of the subject.

In some embodiments, the nucleic acid information is obtained from an in silico analysis.

In some embodiments, the subject is a human subject.

In some embodiments, the polynucleic acid sample comprises a polynucleic acid from blood, saliva, urine, serum, tears, skin, tissue, or hair of the subject.

In some embodiments, the method further comprises analyzing for a presence of JCV in a biological sample from the subject.

In some embodiments, the analyzing for a presence of JCV comprises contacting a JCV detection reagent to the biological sample.

In some embodiments, the JCV detection reagent is selected from the group consisting of an anti-JCV antibody, a JCV specific primer, and combinations thereof.

Provided herein is a kit, comprising reagents for assaying a polynucleic acid sample from a subject in need thereof for the presence of one or more genetic variations that disrupt or modulate a gene of GN1-GN490.

In some embodiments, the reagents comprise at least one contiguous oligonucleotide that hybridizes to a fragment of the polynucleic acid sample.

In some embodiments, the reagents comprise at least one pair of oligonucleotides that hybridize to opposite strands of a fragment of the polynucleic acid sample.

In some embodiments, the kit further comprises one or more immunosuppressive medications.

In some embodiments, the one or more immunosuppressive medications comprise a glucocorticoid, cytostatic, antibody, drug acting on immunophilins, interferon, opioid, TNF binding protein, mycophenolate, small biological agent, or any combination thereof.

In some embodiments, the one or more immunosuppressive medications comprise an interferon beta-1a, interferon beta-1b, glatiramer acetate, peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone, rituximab, natalizumab, daclizumab, ocrelizumab, siponimod or any combination thereof.

In some embodiments, the one or more immunosuppressive medications comprise natalizumab (e.g., TYSABRI).

In some embodiments, the kit further comprises a JCV detection reagent.

In some embodiments, the JCV detection reagent is selected from the group consisting of an anti-JCV antibody, a JCV specific primer, and combinations thereof.

In some embodiments, the kit further comprises a set of instructions for administration of the one or more immunosuppressive medications.

In some embodiments, the one or more genetic variations comprise a point mutation, polymorphism, single nucleotide polymorphisms (SNP), single nucleotide variation (SNV), translocation, insertion, deletion, amplification, inversion, interstitial deletion, copy number variation (CNV), structural variation (SV), loss of heterozygosity, or any combination thereof.

In some embodiments, the one or more genetic variations result in a loss of function of the corresponding gene.

In some embodiments, the one or more genetic variations comprise 5 or more genetic variations.

In some embodiments, the one or more genetic variations comprise 10 or more genetic variations.

In some embodiments, the one or more genetic variations comprise 20 or more genetic variations.

In some embodiments, the one or more genetic variations comprise 50 or more genetic variations.

In some embodiments, the subject is a human subject.

In some embodiments, the polynucleic acid sample comprises a polynucleic acid from blood, saliva, urine, serum, tears, skin, tissue, or hair of the subject.

Provided herein is a panel of polynucleic acids for detecting one or more genetic variations that disrupt or modulate a gene of GN1-GN765, wherein each polynucleic acid of the panel comprises a sequence complementary to a sequence of one or more genetic variation or complements thereof that disrupts or modulates a gene selected from the group consisting of GN1-GN765.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to SEQ ID NOs 1-172, 2200-2203, or SRN1-SRN366, with 100% sequence identity to SEQ ID NOs 1000-1329, 3000-3274, or with at least 80% and less than 100% sequence identity to GN1-GN765, or complements thereof.

In some embodiments, the one or more genetic variations are encoded by a sequence with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to SEQ ID NOs 2200-2203 or SRN364-SRN366, with 100% sequence identity to SEQ ID NOs 3000-3274, or with at least 80% and less than 100% sequence identity to GN491-GN765, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a CNV with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to SEQ ID NOs 1-172, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a CNV with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to SEQ ID NOs 2200-2203, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a CNV sub-region (SRN) with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to SRN1-SRN363, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a CNV sub-region (SRN) with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to SRN364-SRN366, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a single nucleotide variation (SNV) with a sequence of any one of SEQ ID NOs: 1000-1329, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a single nucleotide variation (SNV) with a sequence of any one of SEQ ID NOs: 3000-3274, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a single nucleotide variation (SNV) with a sequence of any one of SEQ ID NO: 3300-3351, 3400-3467 or 3500-3526.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a sequence with at least 80% and less than 100% sequence identity to GN1-GN490, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a sequence with at least 80% and less than 100% sequence identity to GN491-GN765, or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a single nucleotide variation (SNV) with a sequence of any one of SEQ ID NO: 1000, 1001, 1002, 1009, 1010, 1011, 1012, 1014, 1016, 1017, 1019, 1020, 1028, 1032, 1033, 1034, 1035, 1036, 1037, 1040, 1041, 1043, 1051, 1054, 1056, 1057, 1058, 1059, 1061, 1062, 1063, 1066, 1068, 1069, 1070, 1071, 1073, 1074, 1075, 1076, 1077, 1078, 1080, 1082, 1084, 1090, 1092, 1098, 1099, 1100, 1101, 1104, 1107, 1114, 1116, 1118, 1121, 1122, 1123, 1125, 1126, 1127, 1128, 1129, 1130, 1131, 1133, 1135, 1136, 1137, 1138, 1142, 1146, 1147, 1148, 1150, 1152, 1154, 1157, 1160, 1161, 1165, 1166, 1167, 1168, 1169, 1171, 1174, 1175, 1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1193, 1194, 1200, 1201, 1202, 1203, 1204, 1208, 1219, 1220, 1221, 1222, 1226, 1227, 1228, 1229, 1230, 1231, 1232, 1235, 1239, 1247, 1248, 1249, 1250, 1251, 1252, 1254, 1255, 1256, 1259, 1260, 1261, 1263, 1264, 1266, 1267, 1273, 1278, 1279, 1283, 1284, 1286, 1287, 1289, 1290, 1291, 1299, 1300, 1301, 1304, 1311, 1327 or 1328 (see Tables 7 and 8), or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a single nucleotide variation (SNV) with a sequence of any one of SEQ ID NO: 1011, 1020, 1028, 1032, 1034, 1035, 1036, 1040, 1056, 1069, 1073, 1077, 1101, 1114, 1123, 1125, 1126, 1127, 1135, 1142, 1146, 1147, 1148, 1152, 1154, 1157, 1167, 1174, 1184, 1193, 1194, 1203, 1208, 1221, 1222, 1229, 1235, 1252, 1255, 1256, 1259, 1260, 1261, 1263, 1273, 1278, 1279, 1284, 1287, 1289, 1299 or 1311 (see Table 7), or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a single nucleotide variation (SNV) with a sequence of any one of SEQ ID NO: 1000, 1001, 1002, 1009, 1010, 1012, 1014, 1016, 1017, 1019, 1033, 1037, 1041, 1043, 1051, 1054, 1057, 1058, 1059, 1061, 1062, 1063, 1066, 1068, 1070, 1071, 1074, 1075, 1076, 1078, 1080, 1082, 1084, 1090, 1092, 1098, 1099, 1100, 1104, 1107, 1116, 1118, 1121, 1122, 1128, 1129, 1130, 1131, 1133, 1136, 1137, 1138, 1146, 1147, 1150, 1152, 1160, 1161, 1165, 1166, 1168, 1169, 1171, 1175, 1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1200, 1201, 1202, 1204, 1219, 1220, 1226, 1227, 1228, 1230, 1231, 1232, 1239, 1247, 1248, 1249, 1250, 1251, 1252, 1254, 1264, 1266, 1267, 1278, 1279, 1283, 1286, 1290, 1291, 1300, 1301, 1304, 1327 or 1328 (see Table 8), or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a single nucleotide variation (SNV) with a sequence of any one of SEQ ID NO: 3300-3351, 3400-3467 or 3500-3526.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr16:81942175 A>G, chr2:163136505 C>G, chr11:67818269 G>A, chr22:23917192 G>T, chr20:3846397 C>T, chr8:145154222, G>A chr8:61654298 T>A, chr3:39323163 A>C, chr4:151199080 G>A, chr1:42047208 C>G, chr2:163124051 C>T, chr1:182554557 C>T, chr8:145154824 A>C, chr20:62305450 C>T, chr22:23915745 G>A, chr6:83884161 C>G, chr11:108202772 G>T, chr5:138856923 C>T, chr16:1510535 C>T, chr20:3843027 C>A, chr12:122064788 G>GT, chr16:7714909 C>T, chr18:56401523 C>T, chr1:92946625 G>C, chr5:169081453 G>C, chr11:108117787 C>T, chr22:21235389 A>G, chr19:4817657 C>T, chr10:1060218 G>A, chr21:30698953 T>G, chr9:304628 G>A, chr19:7712287 G>C, chr10:90771767 G>A, chr3:121415370 T>C, chr16:70503095 A>G, chr1:206945738 C>T, chr5:156593120 C>T, chr4:27019452 C>T, chr1:155317682 C>T, chr17:77926526 C>T, chr1:235840495 G>T, chr14:21993359 G>A, chr8:61757805 C>T, chr15:91306241 G>A, chr16:50741791 C>T, chr22:23915583 T>C, chr2:47205921 C>T, chr12:88900891 C>A, chr3:142281353 C>G, chr11:108123551 C>T, chr1:207641950 C>T, chr6:143092151 T>C, chr2:24431184 C>T, chr2:24432937 C>T, chr9:312134 G>A, chr8:100205255 G>A, chr21:16339852 T>C, and any combination thereof (see Tables 14 and 15).

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr16:81942175 A>G, chr2:163136505 C>G, chr11:67818269 G>A, chr22:23917192 G>190, chr20:3846397 C>T, chr8:145154222, G>A chr8:61654298 T>A, chr3:39323163 A>C, chr4:151199080 G>A, chr1:42047208 C>G, chr2:163124051 C>T, chr1:182554557 C>T, and any combination thereof (see Table 14).

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr8:145154824 A>C, chr20:62305450 C>T, chr22:23915745 G>A, chr6:83884161 C>G, chr11:108202772 G>T, chr5:138856923 C>T, chr16:1510535 C>T, chr20:3843027 C>A, chr12:122064788 G>GT, chr16:7714909 C>T, chr18:56401523 C>T, chr1:92946625 G>C, chr5:169081453 G>C, chr11:108117787 C>T, chr22:21235389 A>G, chr19:4817657 C>T, chr10:1060218 G>A, chr21:30698953 T>G, chr9:304628 G>A, chr19:7712287 G>C, chr10:90771767 G>A, chr3:121415370 T>C, chr16:70503095 A>G, chr1:206945738 C>T, chr5:156593120 C>T, chr4:27019452 C>T, chr1:155317682 C>T, chr17:77926526 C>T, chr1:235840495 G>T, chr14:21993359 G>A, chr8:61757805 C>T, chr15:91306241 G>A, chr16:50741791 C>T, chr22:23915583 T>C, chr2:47205921 C>T, chr12:88900891 C>A, chr3:142281353 C>G, chr11:108123551 C>T, chr1:207641950 C>T, chr6:143092151 T>C, chr2:24431184 C>T, chr2:24432937 C>T, chr9:312134 G>A, chr8:100205255 G>A, chr21:16339852 T>C, and any combination thereof (see Table 15).

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr1:196759282, C>T, chr4:126412634, C>G, chr10:75673748, A>C, chr6:30675830, T>A, chr6:30680721, G>A, chr12:56385915, GGGA>G, chr18:57103126, G>A, chr3:171321023, C>T, chr1:59131311, G>T, chr22:31008867, T>C, chr2:74690378, C>T, chr17:7592168, C>G, chr2:74690039, G>A, chr12:113448288, A>G, chr17:76130947, G>T, chr2:15674686, T>C, chr2:15607842, T>C, chr14:94847262, T>A, chr4:126412154, G>A, chr22:37271882, T>C, chr20:44640959, G>A, chr17:8138569, C>G, chr12:113357237, G>C, chr12:113357209, G>A, chr11:60893235, C>T, chr12:113357442, G>A, chr5:40964852, A>C, chr14:35497285, T>C, chr19:55494157, G>A, and any combination thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr11:72145307, C>G, chr7:30491421, G>T, chr6:30673403, A>G, chr19:44153248, T>C, chr17:43555253, A>G, chr2:188349523, A>G, chr1:57409459, C>A, chr4:126241248, C>G, chr5:39311336, A>T, chr17:76129619, C>T, chr4:110929301, T>C, chr3:11402163, G>A, chr16:67694044, C>T, chr19:10395141, G>A, chr6:106740989, T>C, chr1:183532364, T>A, chr22:35806756, G>A, chr4:110865044, G>C, chr4:110864533, C>T, chr4:126238090, G>T, chr4:110932508, C>A, chr6:31605016, T>C, chr7:92733766, C>A, chr18:29645930, A>T, and any combination thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr21:45708278, G>A, chr11:108106443, T>A, chr1:57409459, C>A, chr1:196918605, A>G, chr3:58191230, G>T, chr2:230579019, G>A, chr9:137779251, G>A, chr1:27699670, AG>A, chr1:92946625, G>C, chr1:42047208, C>G, chr2:163136505, C>G, chr22:23915583, T>C, chr22:23915745, G>A, chr19:48643270, C>T, chr4:151793903, T>C, chr1:160769595, AG>A, chr22:35806756, G>A, chr6:30673359, T>G, chr6:3015818, G>A, chr6:51798908, C>T, chr16:81942175, A>G, chr19:8564523, T>G, chr14:94847262, T>A, chr19:7712287, G>C, chr6:32814942, C>T, chr6:32816772, C>A and chr11:67818269, G>A.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr22:23915745, G>A, chr6:30673359, T>G, chr19:7712287, G>C, chr9:137779251, G>A, chr22:23915583, T>C, chr22:35806756, G>A and chr2:163136505, C>G. In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr19:8564523, T>G, chr11:108106443, T>A, chr6:32816772, C>A, chr6:32814942, C>T, chr16:81942175, A>G, chr1:27699670, AG>A, chr2:230579019, G>A, chr14:94847262, T>A and chr4:151793903, T>C.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr22:23915745, G>A, chr6:30673359, T>G, chr19:7712287, G>C, chr19:8564523, T>G, chr11:108106443, T>A, chr9:137779251, G>A, chr22:23915583, T>C, chr22:35806756, G>A, chr2:163136505, C>G, chr6:32816772, C>A, chr6:32814942, C>T, chr16:81942175, A>G, chr1:27699670, AG>A, chr2:230579019, G>A, chr14:94847262 and T>A, chr4:151793903, T>C.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr1:160769595, AG>A, chr19:48643270, C>T, chr6:51798908, C>T, chr21-45708278-G-A, chr1:92946625, G>C, chr1:196918605, A>G, chr6:3015818, G>A, chr1:57409459, C>A, chr3:58191230, G>T and chr16:81942175, A>G.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr19:8564523, T>G, chr1:42047208, C>G and chr11:67818269, G>A

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr1:160769595, AG>A, chr19:48643270, C>T, chr6:51798908, C>T, chr21-45708278-G-A, chr1:92946625, G>C, chr1:196918605, A>G, chr6:3015818, G>A, chr19:8564523, T>G, chr1:57409459, C>A, chr3:58191230, G>T, chr16:81942175, A>G, chr1:42047208, C>G and chr11:67818269, G>A.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr6:51798908, C>T, chr1:160769595, AG>A, chr1:196918605, A>G, chr6:3015818, G>A, chr21-45708278-G-A, chr22:23915745, G>A, chr11:67818269, G>A, chr11:108106443, T>A, chr6:30673359, T>G, chr19:8564523, T>G, chr9:137779251, G>A, chr19:7712287, G>C and chr16:81942175, A>G.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr6:32816772, C>A, chr6:32814942, C>T, chr1:92946625, G>C, chr22:23915583, T>C, chr22:35806756, G>A, chr2:163136505, C>G, chr1:27699670, AG>A and chr14:94847262, T>A.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr6:51798908, C>T, chr1:160769595, AG>A, chr1:196918605, A>G, chr6:3015818, G>A, chr21-45708278-G-A, chr22:23915745, G>A, chr11:67818269, G>A, chr11:108106443, T>A, chr6:30673359, T>G, chr19:8564523, T>G, chr9:137779251, G>A, chr19:7712287, G>C, chr16:81942175, A>G, chr6:32816772, C>A, chr6:32814942, C>T, chr1:92946625, G>C, chr22:23915583, T>C, chr22:35806756, G>A, chr2:163136505, C>G, chr1:27699670, AG>A and chr14:94847262, T>A.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr1:160769595, AG>A, chr6:51798908, C>T, chr21-45708278-G-A, chr1:196918605, A>G, chr6:3015818, G>A, chr22:23915745, G>A, chr19:8564523, T>G, chr6:30673359, T>G, chr9:137779251, G>A, chr19:7712287, G>C, chr11:67818269, G>A and chr16:81942175, A>G.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr19:48643270, C>T, chr22:35806756, G>A, chr1:92946625, G>C, chr2:163136505, C>G, chr22:23915583, T>C, chr11:108106443, T>A, chr6:32814942, C>T, chr6:32816772, C>A, chr1:27699670, AG>A, chr4:151793903, T>C and chr14:94847262, T>A.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of chr1:160769595, AG>A, chr6:51798908, C>T, chr21-45708278-G-A, chr1:196918605, A>G, chr6:3015818, G>A, chr22:23915745, G>A, chr19:8564523, T>G, chr6:30673359, T>G, chr9:137779251, G>A, chr19:7712287, G>C, chr11:67818269, G>A, chr16:81942175, A>G, chr19:48643270, C>T, chr22:35806756, G>A, chr1:92946625, G>C, chr2:163136505, C>G, chr22:23915583, T>C, chr11:108106443, T>A, chr6:32814942, C>T, chr6:32816772, C>A, chr1:27699670, AG>A, chr4:151793903, T>C and chr14:94847262, T>A.

In some embodiments, the one or more genetic variations comprises chr21:45708278 G>A, chr14:94847262 T>A, chr1:57409459 C>A, chr22:35806756 G>A, chr11:108106443 T>A, chr1:196918605 A>G, chr3:58191230 G>T, chr2:230579019 G>A, chr9:137779251 G>A, chr1:27699670 AG>A, chr19:48643270 C>T, chr4:151793903 T>C, chr1:160769595 AG>A, chr6:30673359 T>G, chr6:3015818 G>A, chr19:8564523 T>G, chr6:32814942 C>T or chr6:32816772 C>A; wherein chromosome positions of the one or more genetic variations are defined with respect to UCSC hg19.

In some embodiments, the one or more genetic variations do not comprise a genetic variation of chr2:163136505, C>G.

In some embodiments, the one or more genetic variations do not comprise a genetic variation of chr22:23915745, G>A.

In some embodiments, the one or more genetic variations do not comprise a genetic variation of chr16:81942175, A>G.

In some embodiments, the one or more genetic variations do not comprise a genetic variation of chr19:7712287, G>C.

In some embodiments, the one or more genetic variations do not comprise a genetic variation of chr11:67818269, G>A.

In some embodiments, the one or more genetic variations do not comprise a genetic variation of chr2:163136505, C>G; chr22:23915745, G>A; chr16:81942175, A>G; chr19:7712287, G>C; and chr11:67818269, G>A.

In some embodiments, the SNV is a heterozygous SNV.

In some embodiments, the SNV is a homozygous SNV.

In some embodiments, the one or more genetic variations comprise a pair of single nucleotide variations (SNVs), wherein the pair of SNVs are encoded by any one of SEQ ID NO pairs: 1003 and 1004, 1003 and 1005, 1006 and 1007, 1024 and 1025, 1030 and 1031, 1047 and 1048, 1049 and 1050, 1063 and 1064, 1063 and 1065, 1063 and 1066, 1075 and 1076, 1091 and 1093, 1091 and 1096, 1093 and 1095, 1094 and 1097, 1098 and 1099, 1098 and 1100, 1099 and 1100, 1102 and 1103, 1104 and 1106, 1104 and 1107, 1104 and 1108, 1104 and 1109, 1104 and 1110, 1104 and 1111, 1104 and 1112, 1110 and 1111, 1112 and 1113, 1119 and 1120, 1124 and 1125, 1124 and 1126, 1125 and 1126, 1140 and 1141, 1142 and 1144, 1146 and 1151, 1147 and 1148, 1147 and 1149, 1153 and 1146, 1153 and 1147, 1155 and 1156, 1160 and 1161, 1165 and 1166, 1186 and 1187, 1188 and 1193, 1189 and 1193, 1191 and 1192, 1191 and 1193, 1191 and 1195, 1192 and 1193, 1192 and 1195, 1196 and 1197, 1206 and 1207, 1210 and 1218, 1211 and 1213, 1212 and 1213, 1213 and 1215, 1213 and 1216, 1213 and 1217, 1233 and 1238, 1242 and 1243, 1245 and 1246, 1263 and 1260, 1269 and 1279, 1270 and 1279, 1270 and 1282, 1271 and 1279, 1274 and 1279, 1278 and 1279, 1278 and 1281, 1279 and 1280, 1279 and 1281, 1279 and 1282, 1292 and 1293, 1296 and 1297, 1305 and 1314, 1306 and 1310, 1313 and 1321 or 1315 and 1322 (see Table 9 or Tables 9 and 7 for a subset), or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a CNV with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to any one of SEQ ID NOs 157, 2, 140, 65, 26, 14 or 45 (see Tables 7 and 8), or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a CNV with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to any one of SEQ ID NOs 2, 140, 65, 26, 14 or 45 (see Table 7), or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a CNV with at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to SEQ ID NO 157 (see Table 8), or a complement thereof

In some embodiments, the one or more genetic variations comprise a CNV and a single nucleotide variations (SNV), wherein SNVs is encoded by any one of SEQ ID NOs 1301, 1173, 1107, 1104, 1199, 1225, 1086 or 1223 (see Table 10), or complements thereof.

In some embodiments, the one or more genetic variations comprise a genetic variation selected from the group consisting of one or more of the following: chr8:145154222 G>A, chr2:163136505 C>G, chr16:81942175 A>G, and chr8:61654298 T>A (see Tables 14 and 16).

In some embodiments, the one or more genetic variations disrupt or modulate one or more of the following genes: PLCG2, POLE, LRBA, EPG5 and SHARPIN (see Table 17).

In some embodiments, the one or more genetic variations disrupt or modulate one or more of the following genes: PLCG2, CHD7, IFIH1, AP3B1, EPG5, PIK3CD, LRBA and SHARPIN (see Table 18).

In some embodiments, the gene encodes a transcript with a sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to any one of SEQ ID NOs 173-455, 1500-2177, 2204-2215, 2300-2893 (see Tables 4, 12, 30, and 32), or complements thereof.

In some embodiments, the gene encodes a transcript with a sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to any one of SEQ ID NOs 173-455 (see Table 4), or complements thereof.

In some embodiments, the gene encodes a transcript with a sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to any one of SEQ ID NOs 1500-2177 (see Table 12), or complements thereof.

In some embodiments, the gene encodes a transcript with a sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to any one of SEQ ID NOs 2204-2215, or complements thereof.

In some embodiments, the gene encodes a transcript with a sequence that has at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% sequence identity to any one of SEQ ID NOs 2300-2893, or complements thereof.

In some embodiments, the one or more genetic variations comprise at least 5, at least 10, at least 20, or at least 50 genetic variations.

In some embodiments, panel of polynucleic acids comprises at least 5, at least 10, at least 20, or at least 50 polynucleic acids.

In some embodiments, the gene comprises a gene selected from the group consisting of gene numbers (GNs) 1-156 (in Table 3).

In some embodiments, the gene comprises a gene selected from the group consisting of gene numbers (GNs) in Table 6.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of gene numbers (GNs) GN491-GN492 in Table 29.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of gene numbers (GNs) GN493-GN762 in Table 31.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of gene numbers (GNs) GN763-GN765 in Table 48.

In some embodiments, the corresponding gene comprises a gene selected from Tables 34-40, 42, 45A, 45B, 45C, 48, 50A, 50B and 51-62.

In some embodiments, the gene comprises a gene selected from the group consisting of PLCG2, RBCK1, EPG5, IL17F, SHARPIN, PRF1, JAGN1, TAP1, POLE, LRBA, EHF, IL12B, ATL2, NHEJ1, LYST, HIVEP1, AP3B1, TNFRSF10A, PIK3CD, PNP, MCEE, DOCK2 and ALG12 (see Table 13).

Provided herein is a method to predict an adverse responsiveness of a subject to a therapy, the method comprising detecting one or more genetic variations that disrupt or modulate a gene of GN1-GN765 in a polynucleic acid sample from the subject; and using that detection as a biomarker for predicting a response of the subject to the therapy to be adverse, wherein the therapy is an immunosuppressive therapy.

Provided herein is a method of screening for a PML biomarker comprising obtaining biological samples from subjects with PML; screening the biological samples to obtain nucleic acid information; detecting one or more genetic variations that disrupt or modulate a gene of GN1-GN765 in a polynucleic acid sample from a subject suspected of having PML; and using that detection as a biomarker for predicting a response of the subject to the therapy to be adverse, wherein the therapy is an immunosuppressive therapy.

Provided herein is a method of screening for a PML biomarker comprising obtaining biological samples from subjects with PML; screening the biological samples to obtain nucleic acid information; confirming each biological sample is not a duplicate of any other biological sample based on the nucleic acid information; detecting one or more genetic variations that disrupt or modulate a gene of GN1-GN765 in a polynucleic acid sample from a subject suspected of having PML; and using that detection as a biomarker for predicting a response of the subject to the therapy to be adverse, wherein the therapy is an immunosuppressive therapy.

Provided herein is a method of screening for a PML biomarker comprising obtaining biological samples from subjects with PML; screening the biological samples to obtain nucleic acid information; determining a sex genotype for each biological sample based on the nucleic acid information; confirming the sex genotype of each sample is the same as a sex phenotype of the subject from the subjects with PML; detecting one or more genetic variations that disrupt or modulate a gene of GN1-GN765 in a polynucleic acid sample from a subject suspected of having PML; and using that detection as a biomarker for predicting a response of the subject to the therapy to be adverse, wherein the therapy is an immunosuppressive therapy.

Provided herein is a method of treating a condition in a subject in need of natalizumab, interferon beta-1a, interferon beta-1b, glatiramer acetate, peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone, rituximab, daclizumab, ocrelizumab, diroximel fumarate or siponimod therapy, comprising: administering a therapeutically effective amount of natalizumab, interferon beta-1a, interferon beta-1b, glatiramer acetate, peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone, rituximab, daclizumab, ocrelizumab, diroximel fumarate or siponimod to the subject, wherein the subject has a decreased risk of progressive multifocal leukoencephalopathy (PML) due to an infection of the brain by John Cunningham virus (JCV), wherein the subject's decreased risk is due to the absence of one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 29 and 31.

In some embodiments, the subject is identified as not having one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 29 and 31. In some embodiments, the subject is known as not having one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 29 and 31. In some embodiments, the subject is identified in a report (e.g., health report) as not having one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 29 and 31.

Also disclosed is a method of treating a condition in a subject in need of immunosuppressive medication therapy, comprising: administering a therapeutically effective amount of one or more immunosuppressive medications to the subject, wherein the subject has a decreased risk of progressive multifocal leukoencephalopathy (PML) due to an infection of the brain by John Cunningham virus (JCV), wherein the subject's decreased risk is due to the absence of one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 29 and 31.

Also disclosed is a method of treating a condition in a subject in need of natalizumab therapy, comprising: administering a therapeutically effective amount of natalizumab to the subject, wherein the subject has a decreased risk of progressive multifocal leukoencephalopathy (PML) due to an infection of the brain by John Cunningham virus (JCV), wherein the subject's decreased risk is associated with an absence of one or more genetic variations in the subject, wherein the subject has been tested for a presence of the one or more genetic variations with a genetic assay and has been identified as not having the one or more genetic variations, wherein the one or more genetic variations have an odds ratio (OR) of 3 or more, and wherein the OR is: [D_(D)/D_(N)]/[N_(D)/N_(N)], wherein: D_(D) is the number of subjects in a diseased cohort of subjects with the one or more genetic variations; D_(N) is the number of subjects in the diseased cohort without the one or more genetic variations; N_(D) is the number of subjects in a non-diseased cohort of subjects with the one or more genetic variations; and N_(N) is the number of subjects in the non-diseased cohort without the one or more genetic variations, wherein the diseased cohort of subjects have PML, and wherein the non-diseased cohort of subjects do not have PML.

In some embodiments, the one or more genetic variations have an OR of at least 4, 5, 6, 7, 8, 9, or 10.

In some embodiments, the one or more genetic variations occur in one or more immune function-related genes.

In some embodiments, the one or more immunosuppressive medications comprise a glucocorticoid, cytostatic, antibody, drug acting on immunophilins, interferon, opioid, TNF binding protein, mycophenolate, small biological agent, small molecule, organic compound, or any combination thereof.

In some embodiments, the one or more immunosuppressive medications comprise A2aR antagonist, Akt inhibitor, anti CD20, Anti-amyloidotic (AA) Agent, anti-CD37 protein therapeutic, anti-CTLA4 mAb, Anti-CXCR4, anti-huCD40 mAb, anti-LAG3 mAb, anti-PD-1 mAb, anti-PD-L1 agent, anti-PD-L1 agent, anti-PD-L1 mAb, anti-TGFb mAb, anti-TIGIT mAb, anti-TIM-3 mAb, Aurora kinase inhibitor, Bcl-2 Inhibitor, bifunctional fusion protein targeting TGFb and PD-L1, bispecific anti-PD-1 and anti-LAG3 mAb, CD1d ligand, CD40 agonist, Complement C5a inhibitor, CSF1R inhibitor, EZH2 inhibitor, FGFR3 inhibitor, FGFR4 inhibitor, FGFrR3 inhibitor, glucocorticoid-induced tumor necrosis factor receptor-related gene [GITR] agonist, glutaminase inhibitor, Human monoclonal antibody against IL-12, ICOS agonist, IDO1 inhibitor, IL2 mutein, IL2 receptor agonist, MEK inhibitor, multitargeted receptor tyrosine kinase inhibitor, neutrophil elastase inhibitor, Notch Inhibitor, p38 MAPK inhibitor, PD-1 inhibitor, recombinant human Flt3L, ROCK inhibitor, selective sphingosine-1-phosphate receptor modulator, Src kinase inhibitor, TLR4 agonist, TLR9 agonist, or any combination thereof.

In some embodiments, the one or more immunosuppressive medications comprise abatacept (e.g. ORENCIA), abrilumab, acalabrutinib, adalimumab, adrenocorticotropic hormone, agatolimod sodium, AJM300, aldesleukin, alefacept, alemtuzumab, alisertib, alvespimycin hydrochloride, alvocidib, ambrisentan (e.g. LETAIRIS), aminocamptothecin, amiselimod, anakinra, andecaliximab, andrographolides (a botanical medicinal herb also known as IB-MS), anifrolumab, antithymocyte Ig, apatinib, apelisib, asparaginase, atacicept, atezolizumab, avelumab, azacitidine, azathioprine, bafetinib, baminercept, baricitinib, basiliximab, becatecarin, begelomab, belatacept, belimumab, bemcentinib, bendamustine, bendamustine (e.g. bendamustine hydrochloride), betalutin with lilotomab, bevacizumab, BIIB033, BIIB059, BIIB061, bimekizumab, binimetinib, bleomycin, blinatumomab, BNZ-1, bortezomib (e.g. VELCADE), brentuximab vedotin, bryostatin 1, bucillamine, buparlisib, busulfan, canakinumab, capecitabine, carboplatin, carfilzomib, carmustine, cediranib maleate, cemiplimab, ceralifimod, cerdulatinib, certolizumab (e.g. certolizumab pegol), cetuximab, chidamide, chlorambucil, CHS-131, cilengitide, cirmtuzumab, cisplatin, cladribine, clazakizumab, clemastine, clioquinol, corticosteroids, cyclophosphamide, cyclosporine, cytarabine, cytotoxic chemotherapy, daclizumab, dalfampridine (e.g. AMPYRA), daprolizumab pegol, daratumumab, dasatinib, defactinib, defibrotide, denosumab, dexamethasone, diacerein, dimethyl fumarate, dinaciclib, diroximel fumarate (e.g. VUMERITY), doxorubicin, doxorubicin (e.g. doxorubicin hydrochloride), durvalumab, duvelisib, duvortuxizumab, eculizumab (e.g. SOLIRIS), efalizumab, eftilagimod alpha, EK-12 (a neuropeptide combination of metenkefalin and tridecactide), elezanumab, elotuzumab (e.g. EMPLICITI), encorafenib, enfuvirtida (e.g. FUZEON), entinostat, entospletinib, enzastaurin, epacadostat, epirubicin, epratuzumab, eritoran tetrasodium, etanercept, etoposide, etrolizumab, everolimus, evobrutinib, filgotinib, fingolimod (e.g. fingolimod hydrochloride), firategrast, fludarabine, fluorouracil, fontolizumab, forodesine hydrochloride, fostamatinib, galunisertib, ganetespib, ganitumab, gemcitabine, gemtuzumab ozogamicin, gerilimzumab, glasdegib, glassia, glatiramer acetate, glembatumumab vedotin, glesatinib, golimumab (e.g. SIMPONI), guadecitabine, hydrocortisone, hydroxychloroquine sulfate, hydroxyurea, ibritumomab tiuxetan, ibrutinib, ibudilast, idarubicin, idebenone, idelalisib, ifosfamide, iguratimod, imatinib, imexon, IMU-838, infliximab, inotuzumab ozogamicin, interferon alfa-2, interferon beta-1a, interferon beta-1b, interferon gamma-1, ipilimumab, irofulven, isatuximab, ispinesib, itacitinib, ixazomib, lapatinib, laquinimod, laromustine, ld-aminopterin, leflunomide, lenalidomide, lenvatinib, letrozole (e.g. FEMARA), levamisole, levocabastine, lipoic acid, lirilumab, lonafamib, lumiliximab, maraviroc (e.g. SELZENTRY), masitinib, mavrilimumab, melphalan, mercaptopurine, methotrexate, methoxsalen, methylprednisone, milatuzumab, mitoxantrone, mizoribine, mocetinostat, monalizumab, mosunetuzumab, motesanib diphosphate, moxetumomab pasudotox, muromonab-CD3, mycophenolate mofetil (e.g. mycophenolate mofetil hydrochloride), mycophenolic acid, namilumab, natalizumab, navitoclax, neihulizumab, nerispirdine, neurovax, niraparib, nivolumab, obatoclax mesylate, obinutuzumab, oblimersen sodium, ocrelizumab, ofatumumab, olokizumab, opicinumab, oprelvekin, osimertinib, otelixizumab, oxaliplatin, oxcarbazepine, ozanimod, paclitaxel, pacritinib, palifermin, panobinostat, pazopanib, peficitinib, pegfilgrastim (e.g. NEULASTA), peginterferon beta-1a, pegsunercept (peg stnf-ri), pembrolizumab, pemetrexed, penclomedine, pentostatin, perifosine, pevonedistat, pexidartinib, picoplatin, pidilizumab, pivanex, pixantrone, pleneva, plovamer acetate, polatuzumab vedotin, pomalidomide, ponatinib, ponesimod, prednisone/prednisolone, pyroxamide, R-411, ravulizimab-cwvz (e.g. (ULTOMIRIS), recombinant it-12, relatlimab, rhigf-1, rhigm22, rigosertib, rilonacept, ritonavir (e.g. NORVIR), rituximab, ruxolitinib, SAR442168/PRN2246, sarilumab, secukinumab, selumetinib, simvastatin, sintilimab, siplizumab, siponimod (e.g. MAYZENT), sirolimus (rapamycin), sirukumab, sitravatinib, sonidegib, sorafenib, sotrastaurin acetate, sunitinib, sunphenon epigallocatechin-gallate, tabalumab, tacrolimus (e.g. tacrolimus anhydrous), talabostat mesylate, talacotuzumab, tanespimycin, tegafur/gimeracil/oteracil, temozolomide, temsirolimus, tenalisib, terameprocol, teriflunomide, thalidomide, thiarabine, thiotepa, tipifarnib, tirabrutinib, tislelizumab, tivozanib, tocilizumab, tofacitinib, TR-14035, tregalizumab, tremelimumab, treosulfan, ublituximab, umbralisib, upadacitinib, urelumab, ustekinumab, varlilumab, vatelizumab, vedolizumab, veliparib, veltuzumab, venetoclax, vinblastine, vincristine, vinorelbine ditartrate, visilizumab, vismodegib, vistusertib, voriconazole (e.g. VFEND), vorinostat, vosaroxin, ziv-aflibercept, or any combination thereof.

In some embodiments, the one or more immunosuppressive medications comprise 2B3-201, 3PRGD2, 4SC-202, 506U78, 6,8-bis(benzylthio)octanoic acid, 68Ga-BNOTA-PRGD2, 852A, 89Zr-DFO-CZP, ABBV-257, ABL001, ABP 501, ABP 710, ABP 798, ABT-122, ABT-199, ABT-263, ABT-348, ABT-494, ABT-555, ABT-874, ABX-1431 HCl, ACP-196, ACP-319, ACT-128800, ACY-1215, AD 452, Ad-P53, ADCT-301, ADCT-402, ADL5859, ADS-5102, AFX-2, AGEN1884, AGEN2034, AGS67E, AIN457, AK106-001616, ALD518, ALKS 8700, ALT-803, ALT-803, ALX-0061, ALXN1007, ALXN6000, AMD3100, AMG 108, AMG 319, AMG 357, AMG 570, AMG 592, AMG 714, AMG 719, AMG 827, AMP-110, AP1903, APL A12, AP0866, APX005M, AQ4N, AR-42, ARN-6039, ARQ 531, ARRY-371797, ARRY-382, ARRY-438162, ART-I02, ART621, ASK8007, ASNO02, ASP015K, ASP1707, ASP2408, ASP2409, ASP5094, AT-101, AT7519M, AT9283, ATA188, ATN-103, ATX-MS-1467, AVL-292, AVP-923, AZD4573, AZD5672, AZD5991, AZD6244, AZD6738, AZD9056, AZD9150, AZD9567, AZD9668, B-701, BAF312, BAY1830839, BBI608, BCD-054, BCD-055, BCD-063, BCD-089, BCD-100, BCD-132, BCD-145, BEZ235, BG00012, BG9924, BGB-3111, BGB-A333, BGG492, BHT-3009, BI 655064, BI 695500, BI 695501, BI 836826, BI-1206, MBR 796 BS, BIIB017, BIIB023, BIIB057, BIIB061, BIIL 284 BS, BLZ945, BMMNC, BMN 673, BMS-247550, BMS-582949, BMS-817399, BMS-936558, BMS-936564, BMS-945429, BMS-986104, BMS-986142, BMS-986156, BMS-986195, BMS-986205, BMS-986213, BMS-986226, BMS-986251, BNC105P, BOW015, BP1001, BT061, BTT-1023, C105, CAL-101, CAM-3001, CAT-8015, CB-839, CBL0137, CC-1088, CC-115, CC-122, CC-292, CC100, CCI-779, CCX 354-C, CDKI AT7519, CDP323, CDP6038, CDP870, CDX-1127, CDX-301, CE-224535, CF101, CFZ533, CGP 77116, CH-1504, CH-4051, CHR-5154, CHS-0214, CK-2017357, CLAG-M, CLR 131, CMAB008, CMP-001, CNF2024 (BIIB021), CNM-Au8, CNTO 1275, CNTO 136, CNTO 148, CNTO 6785, CP-195543, CP-461, CpG 7909, CPI-1205, CR6086, CRx-102, CS-0777, CS1002, CT-011, CT-1530, CT-P10, CV301, CX-3543, DAC-HYP, DCDT2980S, DI-B4, DPA-714 FDG, DS-3032b, DT2219ARL, DTRM-505, DTRM-555, DTRMWXHS-12, DWP422, E6011, E7449, EK-12, ELND002, ENIA11, EOC202, ETBX-011, F8IL10, FBTA05, FEDAA1106 (BAY85-8101), FGF401, FKB327, FPA008, FR104, FS118, FTY720, G100, GCS-100, GDC-0199, GDC-0853, GEH120714, GLPG0259, GLPG0634, GNbAC1, GNKG168, GP2013, GP2015, GRN163L, GS-1101, GS-5745, GS-9219, GS-9820, GS-9876, GS-9901, GSK1223249, GSK1827771, GSK2018682, GSK21110183, GSK239512, GSK2618960, GSK2831781, GSK2982772, GSK3117391, GSK3152314A, GSK3196165, GSK3358699, GSK706769, GW-1000-02, GW274150, GW406381, GW856553, GZ402668, HCD122, HE3286, HL2351, HL237, hLL1-DOX (IMMU-115), HLX01, HM71224, HMPL-523, HSC835, HZT-501, ICP-022, IDEC-C2B8, ILV-094, IMGN529, IMMU-114, IMO-2125, INCAGN02385, INCB018424, INCB028050, INCB039110, INCB047986, INCMGA00012, INNO-406, INT131, INT230-6, INVAC-1, IPI-145, IPX056, ISF35, ISIS 104838, ITF2357, JCARH125, JHL1101, JNJ 38518168, JNJ-39758979, JNJ-40346527, JNJ-63723283, JS001, JTE-051, JTX-2011, KB003, KD025, KPT-330, KW-2449, KW-2478, KX2-391, L-778123, LAG525, LAM-002A, LBEC0101, LBH589, LFB-R603, LMB-2, LX3305, LY2127399, LY2189102, LY2439821, LY3009104, LY3090106, LY3300054, LY3321367, LY3337641, M2951, M7824, M923, MBG453, MBP8298, MBS2320, MD1003, MDG013, MDV9300, MDX-1100, MDX-1342, MDX-1411, ME-401, MEDI-522, MEDI-538, MEDI-551, MEDI4920, MGA012, MGCD0103, MGD007, MIS416, MK-0873, MK-4280, MK-4827, MK-8457, MK-8808, MK0359, MK0457, MK0752, MK0782, MK0812, MK2206, MLN1202, MLTA3698A, MM-093, MN-122, MN-166, monoclonal antibody M-T412, monoclonal antibody mono-dgA-RFB4, MOR00208, MOR103, MORAb-022, MP-435, MP470, MRC375, MRG-106, MS-533, MSB11022, MSC2490484A, MT-1303, MT-3724, MTIG7192A, MTRX1011A, NBI-5788, NC-503, NI-0101, NI-071, NIS793, NKTR-214, NNC 0141-0000-0100, NNC 0151-0000-0000, NNC0109-0012, NNC0114-0000-0005, NNC0114-0006, NNC0142-0002, NNCO215-0384, NNC109-0012, NOX-A12, NT-KO-003, NU100, OMB157, OMP-313M32, ON01910 Na, ONO-2506P0, ONO-4641, ONTAK, OPB 31121, OSI-461, OTS167IV, P1446A-05, PBF-509, PBRO6, PCI 32765, PCI-24781, PD 0360324, PDA001, PDR001, PF-04171327, PF-04236921, PF-04308515, PF-04629991, PF-05280586, PF-06342674, PF-06410293, PF-06438179, PF-06650833, PF-06651600, PF-06835375, PG-760564, PH-797804, PLA-695, PLX3397, PLX5622, POL6326, PRO131921, PRO283698, PRTX-100, PS-341, PTL201, R(+)XK469, R788, RAD001, RC18, REGN1979, REGN3767, REGN2810, REGN4659, RFT5-SMPT-dgA, RG2077, RGB-03, RGI-2001, RHB-104, RNS60, RO5045337, RO7123520, Rob 803, RPC1063, RWJ-445380, S 55746, SAIT101, SAN-300, SAR245409, SB-681323, SB683699, SBI-087, SC12267 (45C-101), SCH 727965, SCIO-469, SD-101, SG2000, SGN-40, SHC014748M, SHR-1210, SHR0302, SHR1020, SJG-136, SKI-O-703, SMP-114, SNS-032, SNS-062, SNX-5422, SPARC1103 I, SPC2996, SSR150106, STA 5326 mesylate, Sunpharma1505, SyB L-0501, Sym022, Sym023, SYN060, T-614, T0001, TA-650, TAB08, TAK-715, TAK-783, TAK-901, TGR-1202, TH-302, TL011, TMI-005, TMP001, TNFa Kinoid, TP-0903, TRU-015, TRU-016, TSR-022, TSR-033, TSR-042, TXA127, VAY736, VP-16, VSN16R, VX-509, VX-702, VX-745, VX15/2503, XCEL-MC-ALPHA, XL228, XL844, XmAb13676, XmAb5574, XOMA 052, YRA-1909, Z102, ZEN003365, or any combination thereof.

In some embodiments, the one or more immunosuppressive medications comprise interferon beta-1a, interferon beta-1b, glatiramer acetate, peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone, rituximab, natalizumab, daclizumab, ocrelizumab, diroximel fumarate, siponimod or any combination thereof. In some embodiments, the one or more immunosuppressive medications comprises natalizumab.

In some embodiments, the one or more immunosuppressive medications comprise an antibody molecule or a fragment thereof. In some embodiments, the antibody molecule or a fragment thereof is a recombinant antibody molecule or a fragment thereof. In some embodiments, the antibody molecule or a fragment thereof is a humanized antibody molecule or a fragment thereof. In some embodiments, the antibody molecule or fragment thereof is a humanized recombinant antibody molecule or fragment thereof. In some embodiments, the antibody molecule or fragment thereof is a humanized recombinant IgG4κ monoclonal antibody molecule or fragment thereof. In some embodiments, the antibody molecule or fragment thereof comprises a sequence in CAS Registry Number: 189261-10-7. In some embodiments, the antibody molecule or fragment thereof comprises at least one antibody heavy chain. In some embodiments, the antibody molecule or fragment thereof comprises two antibody heavy chains. In some embodiments, the antibody molecule or fragment thereof comprises at least one antibody light chain. In some embodiments, the antibody molecule or fragment thereof comprises two antibody light chains. In some embodiments, the antibody molecule or fragment thereof comprises at least one antibody heavy chain and at least one antibody light chain.

In some embodiments, the antibody molecule or fragment thereof is produced in myeloma cells. In some embodiments, the antibody molecule or fragment thereof is produced in rabbit hybridoma cells.

In some embodiments, the antibody molecule or fragment thereof binds a receptor. In some embodiments, the antibody molecule or fragment thereof binds an integrin. In some embodiments, the integrin is expressed on surface of a leukocyte. In some embodiments, the leukocyte is a neutrophil. In some embodiments, the leukocyte is not a neutrophil. In some embodiments, the antibody molecule or a fragment thereof binds α4β1 integrin, α4β7 integrin, or both. In some embodiments, the antibody molecule or a fragment thereof binds α4-subunit of α4β1 integrin, α4β7 integrin, or both. In some embodiments, the antibody molecule or a fragment thereof inhibits α4-mediated adhesion of a leukocyte to its receptor.

In some embodiments, the one or more immunosuppressive medications comprise an antibody or a fragment thereof, which comprises a sequence that has at least about 50%, 60%, 70%, 80%, 90%, 95%, or 100% sequence identity to SEQ ID NO. 3275 (QVQLVQSGAE VKKPGASVKV SCKASGFNIK DTYIHWVRQA PGQRLEWMGR IDPANGYTKY DPKFQGRVTI TADTSASTAY MELSSLRSED TAVYYCAREG YYGNYGVYAM DYWGQGTLVT VSSASTKGPS VFPLAPCSRS TSESTAALGC LVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG TKTYTCNVDH KPSNTKVDKR VESKYGPPCP SCPAPEFLGG PSVFLFPPKP KDTLMISRTP EVTCVVVDVS QEDPEVQFNW YVDGVEVHNA KTKPREEQFN STYRVVSVLT VLHQDWLNGK EYKCKVSNKG LPSSIEKTIS KAKGQPREPQ VYTLPPSQEE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SRLTVDKSRW QEGNVFSCSV MHEALHNHYT QKSLSLSLGK). In some embodiments, the antibody or fragment thereof comprises a sequence that has about 50%-100% identity, for example, about 50%-60%, about 50%-70%, about 60%-70%, about 60%-80%, about 70%-80%, about 70%-90%, about 80%-90%, about 80%-95%, about 90%-95%, about 90%-99%, about 90%-100%, about 95%-99%, or about 99%-100% sequence identity to SEQ ID NO. 3275.

In some embodiments, the one or more immunosuppressive medications comprise an antibody or a fragment thereof, which comprises a sequence that has at least about 50%, 60%, 70%, 80%, 90%, 95%, or 100% sequence identity to SEQ ID NO. 3276 (DIQMTQSPSS LSASVGDRVT ITCKTSQDIN KYMAWYQQTP GKAPRLLIHY TSALQPGIPS RFSGSGSGRD YTFTISSLQP EDIATYYCLQ YDNLWTFGQG TKVEIKRTVA APSVFIFPPS DEQLKSGTAS VVCLLNNFYP REAKVQWKVD NALQSGNSQE SVTEQDSKDS TYSLSSTLTL SKADYEKHKV YACEVTHQGL SSPVTKSFNRGEC). In some embodiments, the antibody or fragment thereof comprises a sequence that has about 50%-100% identity, for example, about 50%-60%, about 50%-70%, about 60%-70%, about 60%-80%, about 70%-80%, about 70%-90%, about 80%-90%, about 80%-95%, about 90%-95%, about 90%-99%, about 90%-100%, about 95%-99%, or about 99%-100% sequence identity to SEQ ID NO. 3276.

In some embodiments, the antibody molecule or fragment thereof comprises at least one antibody heavy chain, or an α4-binding fragment thereof, comprising non-human CDRs at positions 31-35 (CDR1), 50-65 (CDR2) and 95-102 (CDR3) (Kabat numbering) from a mouse anti-α4 antibody and having non-human residues at framework positions 27-30 (Kabat numbering), wherein the positions 27-30 have the amino acid sequence Phe 27, Asn 28, Ile 29 and Lys 30.

In some embodiments, the antibody molecule or fragment thereof comprises at least one antibody light chain, or an α4-binding fragment thereof, comprising: a light chain (LC) CDR1 with an amino acid sequence of SEQ ID NO.: 3277 (KTSQDINKYMA), a LC CDR2 with an amino acid sequence of SEQ ID NO.: 3278 (YTSALQP), and a LC CDR3 with an amino acid sequence of SEQ ID NO.: 3279 (LQYDNLWT).

In some embodiments, the antibody molecule or fragment thereof comprises at least one antibody light chain, or an α4-binding fragment thereof, comprising: a light chain (LC) CDR1 with an amino acid sequence of SEQ ID NO.: 3280 (QASQDIIKYLN), a LC CDR2 with an amino acid sequence of SEQ ID NO.: 3281 (EASNLQA), and a LC CDR3 with an amino acid sequence of SEQ ID NO.: 3282 (QQYQSLPYT).

In some embodiments, the antibody molecule or fragment thereof comprises at least one antibody light chain, or an α4-binding fragment thereof, comprising: a light chain (LC) CDR1 with an amino acid sequence of SEQ ID NO.: 3283 (KASQSVTNDVA), a LC CDR2 with an amino acid sequence of SEQ ID NO.: 3284 (YASNRYT), and a LC CDR3 with an amino acid sequence of SEQ ID NO.: 3285 (QQDYSSPYT).

In some embodiments, the antibody molecule or fragment thereof comprises at least one antibody heavy chain, or an α4-binding fragment thereof, comprising: a heavy chain (HC) CDR1 with an amino acid sequence of SEQ ID NO.: 3286 (DTYIH), a HC CDR2 with an amino acid sequence of SEQ ID NO.: 3287 (RIDPANGYTKYDPKFQG), and a HC CDR3 with an amino acid sequence of SEQ ID NO.: 3288 (EGYYGNYGVYAMDY).

In some embodiments, the antibody molecule or fragment thereof comprises at least one antibody heavy chain, or an α4-binding fragment thereof, comprising: a heavy chain (HC) CDR1 with an amino acid sequence of SEQ ID NO.: 3289 (DTYMH), a HC CDR2 with an amino acid sequence of SEQ ID NO.: 3290 (RIDPASGDTKYDPKFQV), and a HC CDR3 with an amino acid sequence of SEQ ID NO.: 3291 (DGMWVSTGYALDF).

In some embodiments, the antibody molecule or fragment thereof comprises a humanized heavy chain, or an α4-binding fragment thereof, comprising: a variable heavy chain region selected from the group consisting of:

SEQ ID NO.: 3292 (MDWTWRVFCLLAVAPGAHSQVQLQESGPGLVRPSQTLSLTCTVSGFNIKD TYMHWVRQPPGRGLEWIGRIDPASGDTKYDPKFQVKATITADTSSNQFSLR LSSVTAADTAVYYCADGMWVSTGYALDFWGQGTTVTVSSGES), SEQ ID NO.: 3293 (QVQLQESGPGLVRPSQTLSLTCTVSGFNIKDTYMHWVRQPPGRGLEWIGR IDPASGDTKYDPKFQVRVTMLVDTSSNQFSLRLSSVTSEDTAVYYCADGMW VSTGYALDFWGQGTTVTVSSGES), SEQ ID NO.: 3294 (MDWTWRVFCLLAVAPGAHSQVQLQESGPGLVRPSQTLSLTCTVSGFNIKD TYMHWVKQRPGRGLEWIGRIDPASGDTKYDPKFQVRVTMLVDTSSNQFSLR LSSVTAADTAVYYCADGMWVSTGYALDFWGQGTTVTVSSGES), SEQ ID NO.: 3295 (MDWTWRVFCLLAVAPGAHSQVQLQESGPGLVRPSQTLSLTCTASGFNIKD TYMHWVRQPPGRGLEWIGRIDPASGDTKYDPKFQVRVTMLVDTSSNQFSLR LSSVTAADTAVYYCADGMWVSTGYALDFWGQGTTVTVSSGES), and SEQ ID NO.: 3296 (QVQLVQSGAEVKKPGASVKVSCKASGFNIKDTYIHWVRQAPGQRLEWMGR IDPANGYTKYDPKFQGRVTITADTSASTAYMELSSLRSEDTAVYYCAREGY YGNYGVYAMDWGQGTLVTVSS).

In some embodiments, the antibody molecule or fragment thereof comprises a humanized light chain, or an α4-binding fragment thereof, comprising a variable light chain region selected from the group consisting of:

SEQ ID NO.: 3297 (MGWSCIILFLVATATGVHSDIQLTQSPSSLSASVGDRVTITCKASQSVTN DVAWYQQKPGKAPKLLIYYASNRYTGVPSRFSGSGSGTDFTFTISSLQPED IATYYCQQDYSSPYTFGQGTKVEIKRK), SEQ ID NO.: 3298 (MGWSCIILFLVATATGVHSSIVMTQSPSSLSASVGDRVTITCKASQSVTN DVAWYQQKPGKAPKLLIYYASNRYTGVPDRFSGSGYGTDFTFTISSLQPED IATYYCQQDYSSPYTFGQGTKVEIKRK), SEQ ID NO.: 3299 (MGWSCIILFLVATATGVHSDIQMTQSPSSLSASVGDRVTITCKASQSVTN DVAWYQQKPGKAPKLLIYYASNRYTGVPDRFSGSGYGTDFTFTISSLQPED IATYYCQQDYSSPYTFGQGTKVEIKRK), and SEQ ID NO.: 3300 (DIQMTQSPSSLSASVGDRVTITCKTSQDINKYMAWYQQTPGKAPRLLIHY TSALQPGIPSRFSGSGSGRDYTFTISSLQPEDIATYYCLQYDNLWTFGQGT KVEIKRTV).

In some embodiments, a biological product can be a regulatory agency-approved biological product. For example, the biological product can be approved by the U.S. Food and Drug Administration (FDA) and/or the European medicines Agency (EMA). In some embodiments, the biological product can be a reference product. In some cases, the biological product can be a biosimilar product. In some embodiments, the biological product can be an interchangeable product.

In some embodiments, a biosimilar product can be similar to a reference product (see, e.g. Table 67). In some embodiments, a biosimilar product can have no clinically meaningful differences in terms of safety and effectiveness from the reference product. In some embodiments, a biosimilar product can have the same clinically inactive components. In some embodiments, a biosimilar product can have different clinically inactive components. In some embodiments, a biosimilar product specifically interacts with a substrate and the reference product specifically interacts with the same substrate. In some embodiments, a response rate of human subjects administered the biosimilar product can be 50%-150% of the response rate of human subjects administered the reference product. For example, the response rate of human subjects administered the biosimilar product can be 50%-100%, 50%-110%, 50%-120%, 50%-130%, 50%-140%, 50%-150%, 60%-100%, 60%-110%, 60%-120%, 60%-130%, 60%-140%, 60%-150%, 70%-100%, 70%-110%, 70%-120%, 70%-130%, 70%-140%, 70%-150%, 80%-100%, 80%-110%, 80%-120%, 80%-130%, 80%-140%, 80%-150%, 90%-100%, 90%-110%, 90%-120%, 90%-130%, 90%-140%, 90%-150%, 100%-110%, 100%-120%, 100%-130%, 100%-140%, 100%-150%, 110%-120%, 110%-130%, 110%-140%, 110%-150%, 120%-130%, 120%-140%, 120%-150%, 130%-140%, 130%-150%, or 140%-150% of the response rate of human subjects administered the reference product. In some embodiments, a biosimilar product and a reference product can utilize the same mechanism or mechanisms of action for the condition or conditions of use prescribed, recommended, or suggested in the proposed labeling, but only to extent the mechanism or mechanisms are known for the reference product.

In some embodiments, an interchangeable product can be a biosimilar product that meets additional standards for interchangeability. In some embodiments, an interchangeable product can produce the same clinical result as a reference product in all of the reference product's licensed conditions of use. In some embodiments, an interchangeable product can be substituted for the reference product by a pharmacist without the intervention of the health care provider who prescribed the reference product. In some embodiments, when administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch. In some embodiments, an interchangeable product can be a regulatory agency approved product. In some embodiments, a response rate of human subjects administered the interchangeable product can be 80%-120% of the response rate of human subjects administered the reference product. For example, the response rate of human subjects administered the interchangeable product can be 80%-100%, 80%-110%, 80%-120%, 90%-100%, 90%-110%, 90%-120%, 100%-110%, 100%-120%, or 110%-120 of the response rate of human subjects administered the reference product.

In some embodiments, the condition is multiple sclerosis or Crohn's disease. In some embodiments, the condition is a relapsing form of multiple sclerosis.

In some embodiments, the natalizumab is administered via intravenous infusion. In some embodiments, about 100 mg to about 500 mg of the natalizumab is administered. In some embodiments, about 100 mg to about 500 mg of the natalizumab is administered, for example, about 100 mg to about 200 mg, about 100 mg to about 300 mg, about 100 mg to about 400 mg, about 100 mg to about 500 mg, about 200 mg to about 300 mg, about 200 mg to about 400 mg, about 200 mg to about 500 mg, about 300 mg to about 400 mg, about 300 mg to about 500 mg, or about 400 mg to about 500 mg of the natalizumab is administered. In some embodiments, about 100 mg to about 500 mg of the natalizumab is administered via intravenous infusion. In some embodiments, about 100 mg to about 500 mg of the natalizumab is administered via intravenous infusion in four weeks. In some embodiments, about 300 mg of the natalizumab is administered. In some embodiments, about 300 mg of the natalizumab is administered via intravenous infusion. In some embodiments, about 300 mg of the natalizumab is administered via intravenous infusion in four weeks. In some embodiments, at least about 10 mg of the natalizumab is administered via intravenous infusion in six weeks. In some embodiments, at least about 10 mg of the natalizumab is administered via intravenous infusion in eight weeks. In some embodiments, about 100 mg to about 500 mg of the natalizumab is administered via intravenous infusion in six weeks. In some embodiments, about 100 mg to about 500 mg of the natalizumab is administered via intravenous infusion in eight weeks. In some embodiments, about 300 mg of the natalizumab is administered via intravenous infusion in six weeks. In some embodiments, about 300 mg of the natalizumab is administered via intravenous infusion in eight weeks

In some embodiments, the one or more immunosuppressive medications comprise dimethyl fumarate. In some embodiments, about 100 mg to about 500 mg of the dimethyl fumarate is administered, for example, about 100 mg to about 200 mg, about 100 mg to about 300 mg, about 100 mg to about 400 mg, about 100 mg to about 500 mg, about 200 mg to about 300 mg, about 200 mg to about 400 mg, about 200 mg to about 500 mg, about 300 mg to about 400 mg, about 300 mg to about 500 mg, or about 400 mg to about 500 mg of the dimethyl fumarate is administered. In some embodiments, about 120 mg of the dimethyl fumarate is administered. In some embodiments, about 240 mg of the dimethyl fumarate is administered.

In some embodiments, the one or more immunosuppressive medications comprise diroximel fumarate. In some embodiments, the one or more immunosuppressive medications comprise diroximel fumarate. In some embodiments, about 100 mg to about 500 mg of the diroximel fumarate is administered, for example, about 100 mg to about 200 mg, about 100 mg to about 300 mg, about 100 mg to about 400 mg, about 100 mg to about 500 mg, about 200 mg to about 300 mg, about 200 mg to about 400 mg, about 200 mg to about 500 mg, about 300 mg to about 400 mg, about 300 mg to about 500 mg, or about 400 mg to about 500 mg of the diroximel fumarate is administered. In some embodiments, about 400, 410, 420, 430, 440, 450, 460, 462, 470, 480, 490 or 500 mg of the diroximel fumarate is administered.

In some embodiments, the one or more immunosuppressive medications comprise fingolimod. In some embodiments, about 0.01 mg to about 5 mg of the fingolimod is administered, for example, about 0.01 mg to about 2 mg, about 0.01 mg to about 3 mg, about 0.01 mg to about 4 mg, about 0.01 mg to about 5 mg, about 0.1 mg to about 2 mg, about 0.1 mg to about 3 mg, about 0.1 mg to about 4 mg, about 0.1 mg to about 5 mg, about 0.2 mg to about 3 mg, about 0.2 mg to about 4 mg, about 0.2 mg to about 5 mg, about 0.3 mg to about 4 mg, about 0.3 mg to about 5 mg, about 0.4 mg to about 5 mg, about 0.1 mg to about 0.2 mg, about 0.1 mg to about 0.3 mg, about 0.1 mg to about 0.4 mg, about 0.1 mg to about 0.5 mg, about 0.2 mg to about 0.3 mg, about 0.2 mg to about 0.4 mg, about 0.2 mg to about 0.5 mg, about 0.3 mg to about 0.4 mg, about 0.3 mg to about 0.5 mg, about 0.4 mg to about 0.5 mg, or about 0.4 mg to about 0.6 mg of the fingolimod is administered. In some embodiments, about 0.25 mg or 0.5 mg of the fingolimod is administered.

In some embodiments, the one or more immunosuppressive medications comprise rituximab. In some embodiments, about 100 mg to about 1000 mg of the rituximab is administered, for example, about 100 mg to about 200 mg, about 100 mg to about 300 mg, about 100 mg to about 400 mg, about 100 mg to about 500 mg, about 100 mg to about 600 mg, about 100 mg to about 700 mg, about 100 mg to about 800 mg, about 100 mg to about 900 mg of the rituximab is administered. The dose may be by weight or a fixed dose. In some embodiments, about 250 mg/m², 375 mg/m², 500 mg/m², 500 mg, or 1000 mg of the rituximab is administered. In some embodiments, about 250 mg/m², 375 mg/m², 500 mg/m², 500 mg, or 1000 mg of the rituximab is administered every week, every 2 weeks, every 4 weeks, every 8 weeks, or every 6 months. In some embodiments, about 250 mg/m², 375 mg/m², 500 mg/m², 500 mg, or 1000 mg of the rituximab is administered every 8 weeks or every 6 months for treating MS. The total dose cab be from about 50 and 4000 mg, for example, from about 75 and 3000 mg, from about 100 and 2000 mg, from about 100 and 1000 mg, from about 150 and 1000 mg, or from about 200 and 1000 mg, including doses of about 200, 300, 400, 500, 600, 700, 800, 900, 1000 mg, and 2000 mg. These doses may be given as a single dose or as multiple doses, for example, two to four doses. Such doses may be done by infusions, for example.

In some embodiments, the one or more immunosuppressive medications comprise siponimod. In some embodiments, about 0.1 mg to about 5 mg of the siponimod is administered. In some embodiments, about 1 mg or about 2 mg of the siponimod is administered. In some embodiments, about 1 mg or about 2 mg of the siponimod is administered to a subject with a CYP2C9*1/*3 or CYP2C9*2/*3 genotype.

In some embodiments, the one or more genetic variations are associated with a risk of developing PML in a polynucleic acid sample from the subject. In some embodiments, the one or more genetic variations comprises a first genetic variation and a second genetic variation, wherein the first genetic variation disrupts or modulates a corresponding gene according to Tables 3 and 6, and wherein the second genetic variation disrupts or modulates a corresponding gene according to Tables 25A, 25B, and 26.

In some embodiments, the method comprises testing the subject for a genetic predisposition for PML with a genetic assay. In some embodiments, the genetic assay has a diagnostic yield of at least 5%. In some cases, the genetic assay has a diagnostic yield of at least about 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%. In some cases, the genetic assay has a diagnostic yield of about 1%-5%, 1%-10%, 1%-20%, 5%-10%, 5%-20%, 10%-20%, 10%-30%, 20%-30%, 20%-40%, 30%-40%, 30%-50%, 40%-50%, 40%-60%, 50%-60%, 50%-70%, 60%-70%, 60%-80%, 70%-80%, 70%-90%, 80%-90%, 80%-95%, 90%-95%, 90%-99%, 90%-100%, 95%-99%, or 99%-100%. In some embodiments, the genetic assay has a diagnostic yield of at least 20%.

In some embodiments, the one or more genetic variations disrupt or modulate a corresponding gene according to Tables 13-18. In some embodiments, the one or more genetic variations disrupt or modulate a corresponding gene according to Tables 19-24. In some embodiments, the one or more genetic variations disrupt or modulate a corresponding gene according to Tables 28A, 28B, 29-41, 42, 45A, 45B, 45C, 48, 50A, 50B and 51-62.

In some embodiments, the subject's decreased risk is further due to the absence of one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 25A, 25B, and 26.

In some embodiments, the one or more genetic variations disrupt or modulate a corresponding gene selected from the group consisting of Homo sapiens chromodomain helicase DNA binding protein 7 (CHD7), Homo sapiens interferon induced with helicase C domain 1 (IFIH1), Homo sapiens immunoglobulin lambda like polypeptide 1 (IGLL1), Homo sapiens mitochondrial antiviral signaling protein (MAVS), Homo sapiens phospholipase C gamma 2 (PLCG2), Homo sapiens SHANK-associated RH domain interactor (SHARPIN), Homo sapiens T-cell immune regulator 1, ATPase H+ transporting V0 subunit a3 (TCIRG1), and any combination thereof. In some embodiments, the one or more genetic variations comprise chr8:61654298 T>A, chr2:163136505 C>G, chr22:23917192 G>T, chr20:3846397 C>T, chr16:81942175 A>G, chr8:145154222 G>A, chr11:67818269 G>A, chr8:145154824 A>C, chr22:23915745 G>A, chr20:3843027 C>A, or any combination thereof.

In some embodiments, the one or more genetic variations disrupt or modulate a corresponding gene selected from the group consisting of FCN2, LY9 and PRAM1.

In some embodiments, the corresponding gene comprises a gene selected from the group consisting of gene numbers (GNs) GN1-GN765. In some embodiments, the corresponding gene comprises a gene selected from the group consisting of gene numbers (GNs) GN1-GN241, GN243-GN369, and GN371-GN490.

In some embodiments, the one or more genetic variations are encoded by a sequence with at least 60% sequence identity to SEQ ID NOs 1-172, 2200-2203, or SRN1-SRN366, with 100% sequence identity to SEQ ID NOs 1000-1329, 3000-3274, or with at least 80% and less than 100% sequence identity to GN1-GN765, or complements thereof. In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a CNV with at least 60% sequence identity to SEQ ID NOs 1-172, 2200-2203, or complements thereof. In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a CNV sub-region (SRN) with at least 60% sequence identity to SRN1-SRN366, or complements thereof. In some embodiments, the one or more genetic variations comprise a genetic variation encoded by a single nucleotide variation (SNV) with a sequence of any one of SEQ ID NOs: 1000-1329, 3000-3274, or complements thereof. In some embodiments, the one or more genetic variations are encoded by a sequence with at least 40% sequence identity to SEQ ID NOs 1-172, 2200-2203, or SRN1-SRN366, for example, at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs 1-172, 2200-2203, or SRN1-SRN366, or complements thereof. In some embodiments, the one or more genetic variations are encoded by a sequence with at least 40% sequence identity to SEQ ID NOs 1000-1329, 3000-3274, for example, at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs 1000-1329, 3000-3274, or complements thereof. In some embodiments, the one or more genetic variations are encoded by a sequence with at least 40% and less than 100% sequence identity to GN1-GN765, for example, at least 40% and less than 50%, at least 50% and less than 60%, at least 60% and less than 70%, at least 70% and less than 80%, at least 80% and less than 90%, or at least 90% and less than 100% sequence identity to GN1-GN765, or complements thereof.

In some embodiments, the genetic assay comprises microarray analysis, PCR, sequencing, nucleic acid hybridization, or any combination thereof.

In some embodiments, the method comprises testing the subject with a JCV-antibody test, a CD62L test, or a CSF IgM oligoclonal bands test. In some embodiments, the method comprises testing the subject with the JCV-antibody test, wherein the JCV-antibody test does not detect a presence of JCV. In some embodiments, the method comprises testing the subject with the JCV-antibody test, wherein the JCV-antibody test detects a presence of JCV. In some embodiments, the JCV-antibody test comprises contacting a JCV detection reagent to a biological sample from the subject. In some embodiments, the JCV detection reagent is selected from the group consisting of an anti-JCV antibody, a JCV specific primer, and combinations thereof.

In some embodiments, the subject is identified as not having one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48.

Provided herein is a kit, comprising reagents for assaying a polynucleic acid sample from a subject in need thereof for the presence of one or more genetic variations that disrupt or modulate a gene of GN1-GN765. In some embodiments, the one or more genetic variations disrupt or modulate a gene of GN1-GN241, GN243-GN369, and GN371-GN490.

Provided herein is a method of treating multiple sclerosis or Crohn's disease comprising: (a) testing a subject with multiple sclerosis or Crohn's disease for a genetic predisposition for PML with a genetic assay, wherein the genetic assay has a diagnostic yield of at least 20%, and (b) administering a therapeutically effective amount of natalizumab, interferon beta-1a, interferon beta-1b, glatiramer acetate, peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone, rituximab, natalizumab, daclizumab, ocrelizumab, diroximel fumarate or siponimod to the subject, wherein the testing does not identify the subject as having the genetic predisposition for PML.

In some embodiments, the method further comprises testing the subject with a JCV-antibody test. In some embodiments, the JCV-antibody test does not detect a presence of JCV. In some embodiments, the JCV-antibody test detects a presence of JCV. In some embodiments, the genetic assay tests the subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48.

Provided herein is a method of identifying a subject as not having a risk of developing PML, comprising: (a) analyzing a polynucleic acid sample from the subject for one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48, wherein a genetic variation of the one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3, 6, 25A, 25B, 26, 29, 31 and 48; or Tables 3, 6, 29, 31 and 48 is not present in the polynucleic acid sample; and (b) identifying the subject as not having a risk of developing PML.

Provided herein is a method of treating a condition in a subject in need of natalizumab, interferon beta-1a, interferon beta-1b, glatiramer acetate, peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone, rituximab, natalizumab, daclizumab, ocrelizumab or diroximel fumarate to the subject therapy, comprising: administering a therapeutically effective amount of natalizumab, interferon beta-1a, interferon beta-1b, glatiramer acetate, peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone, rituximab, natalizumab, daclizumab, ocrelizumab, diroximel fumarate or siponimod to the subject to the subject, wherein the subject has a decreased risk of progressive multifocal leukoencephalopathy (PML) due to an infection of the brain by John Cunningham virus (JCV), wherein the subject's decreased risk is associated with an absence of one or more genetic variations in the subject, wherein the subject has been tested for a presence of the one or more genetic variations with a genetic assay and has been identified as not having the one or more genetic variations selected from Table 43.

Provided herein is a method of treating a condition in a subject in need of natalizumab, interferon beta-1a, interferon beta-1b, glatiramer acetate, peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone, rituximab, natalizumab, daclizumab, ocrelizumab or diroximel fumarate to the subject therapy, comprising: administering a therapeutically effective amount of natalizumab, interferon beta-1a, interferon beta-1b, glatiramer acetate, peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone, rituximab, natalizumab, daclizumab, ocrelizumab, diroximel fumarate or siponimod to the subject to the subject, wherein the subject has a decreased risk of progressive multifocal leukoencephalopathy (PML) due to an infection of the brain by John Cunningham virus (JCV), wherein the subject's decreased risk is associated with a presence of one or more genetic variations in the subject, wherein the subject has been tested for a presence of the one or more genetic variations with a genetic assay and has been identified as having the one or more genetic variations selected from Table 44.

DETAILED DESCRIPTION OF THE DISCLOSURE

The details of one or more inventive embodiments are set forth in the accompanying drawings, the claims, and in the description herein. Other features, objects, and advantages of inventive embodiments disclosed and contemplated herein will be apparent from the description and drawings, and from the claims.

As used herein, unless otherwise indicated, the article “a” means one or more unless explicitly otherwise provided for.

As used herein, unless otherwise indicated, terms such as “contain,” “containing,” “include,” “including,” and the like mean “comprising.”

As used herein, unless otherwise indicated, the term “or” can be conjunctive or disjunctive. As used herein, unless otherwise indicated, any embodiment can be combined with any other embodiment.

As used herein, unless otherwise indicated, some inventive embodiments herein contemplate numerical ranges. When ranges are present, the ranges include the range endpoints. Additionally, every subrange and value within the range is present as if explicitly written out.

As used herein, unless otherwise indicated, the term “about” in relation to a reference numerical value and its grammatical equivalents include a range of values plus or minus 10% from that value, such as a range of values plus or minus 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% from that value. For example, the amount “about 10” includes amounts from 9 to 11.

As used herein, unless otherwise indicated, the term “biological product” refers to a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size), or analogous product, or arsphenamine or derivative of arsphenamine (or any trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.

As used herein, unless otherwise indicated, the term “biosimilar product” refers to 1) a biological product having an amino acid sequence that is identical to a reference product; 2) a biological product having a different amino acid sequence (e.g., N- or C-terminal truncations) from a reference product; or 3) a biological product having a different posttranslational modification (e.g., glycosylation or phosphorylation) from a reference product, wherein the biosimilar product and the reference product utilize the same mechanism or mechanisms of action for the prevention, treatment, or cure of a disease or condition.

As used herein, “mechanism of action” refers to an interaction or activity through which a drug product (e.g., a biological product) produces a pharmacological effect.

As used herein, unless otherwise indicated, the term “interchangeable product” refers to a biosimilar product, wherein a response rate of a human subject administered the interchangeable product is from 80% to 120% of the response rate of the human subject administered the reference product.

As used herein, unless otherwise indicated, the term “reference product” refers to 1) a biological product having an amino acid sequence that is identical to a biosimilar product; 2) a biological product having a different amino acid sequence (e.g., N- or C-terminal truncations) from a biosimilar product; or 3) a biological product having a different posttranslational modification (e.g., glycosylation or phosphorylation) from a biosimilar product, wherein the reference product and the biosimilar product utilize the same mechanism or mechanisms of action for the prevention, treatment, or cure of a disease or condition.

As used herein, unless otherwise indicated, any nonproprietary or generic name of a biological product includes the biological product and any biosimilar product thereof. For example, the nonproprietary name, filgrastim, refers to the biological product sold under the trade name NEUPOGEN; it also includes the biosimilar product, filgrastim-sndz, sold under the trade name ZARXIO. In another example, the nonproprietary name, natalizumab, refers to the biological product sold under the trade name TYSABRI; it also includes any biosimilar product of the biological product.

All drug molecules and compounds provided herein include all salts, polymorphs, prodrugs, tautomers, zwitterionic forms, etc. thereof.

Progressive Multifocal Leukoencephalopathy (PML)

Progressive multifocal leukoencephalopathy (PML) is a rare and usually fatal viral disease characterized by progressive damage or inflammation of the white matter of the brain at multiple locations. The cause of PML can be a type of polyomavirus called the John Cunningham (JC) virus (or JCV), which can be harmless except in cases of weakened immune systems. While JCV is present at very high rates in the general population, PML remains a rare disorder, albeit an important one because of the clinical sequelae.

PML can occur in patients with severe immune deficiency, which allows reactivation of the JC virus, such as: 1) most commonly among patients with acquired immune deficiency syndrome (AIDS) that results from infection with human immunodeficiency virus (HIV), 2) patients on immunosuppressive medications like corticosteroids for organ transplant (e.g., renal, liver, lung, and heart) and in people with cancer (e.g., Hodgkin's disease, leukemia, or lymphoma, and myeloproliferative neoplasms such as myelofibrosis), and 3) individuals with autoimmune diseases (e.g., multiple sclerosis, rheumatoid arthritis, psoriasis, and systemic lupus erythematosus) with therapies that depress the immune response. Several immunosuppressive drugs have been reported in the context of drug-induced PML or drug-associated PML. For example, see: Melis et al. CNS Drugs. 2015; 29(10):879-91); Maas et al. J Neurol. 2016 October; 263(10):2004-21; Colin et al. Fundam Clin Pharmacol. 2016 Oct. 13. Immunosuppressive medications can include, but are not limited to, a glucocorticoid, cytostatic, antibody, drug acting on immunophilins, interferon, opioid, TNF binding protein, mycophenolate, small biological agent, small molecule, organic compound, A2aR antagonist, Akt inhibitor, anti CD20, Anti-amyloidotic (AA) Agent, anti-CD37 protein therapeutic, anti-CTLA4 mAb, Anti-CXCR4, anti-huCD40 mAb, anti-LAG3 mAb, anti-PD-1 mAb, anti-PD-L1 agent, anti-PD-L1 agent, anti-PD-L1 mAb, anti-TGFb mAb, anti-TIGIT mAb, anti-TIM-3 mAb, Aurora kinase inhibitor, Bcl-2 Inhibitor, bifunctional fusion protein targeting TGFb and PD-L1, bispecific anti-PD-1 and anti-LAG3 mAb, CD1d ligand, CD40 agonist, Complement C5a inhibitor, CSF1R inhibitor, EZH2 inhibitor, FGFR3 inhibitor, FGFR4 inhibitor, FGFrR3 inhibitor, glucocorticoid-induced tumor necrosis factor receptor-related gene [GITR] agonist, glutaminase inhibitor, Human monoclonal antibody against IL-12, ICOS agonist, IDO1 inhibitor, IL2 mutein, IL2 receptor agonist, MEK inhibitor, multitargeted receptor tyrosine kinase inhibitor, neutrophil elastase inhibitor, Notch Inhibitor, p38 MAPK inhibitor, PD-1 inhibitor, recombinant human Flt3L, ROCK inhibitor, selective sphingosine-1-phosphate receptor modulator, Src kinase inhibitor, TLR4 agonist, TLR9 agonist, abatacept (e.g. ORENCIA), abrilumab, acalabrutinib, adalimumab, adrenocorticotropic hormone, agatolimod sodium, AJM300, aldesleukin, alefacept, alemtuzumab, alisertib, alvespimycin hydrochloride, alvocidib, ambrisentan (e.g. LETAIRIS), aminocamptothecin, amiselimod, anakinra, andecaliximab, andrographolides (a botanical medicinal herb also known as IB-MS), anifrolumab, antithymocyte Ig, apatinib, apelisib, asparaginase, atacicept, atezolizumab, avelumab, azacitidine, azathioprine, bafetinib, baminercept, baricitinib, basiliximab, becatecarin, begelomab, belatacept, belimumab, bemcentinib, bendamustine, bendamustine (e.g. bendamustine hydrochloride), betalutin with lilotomab, bevacizumab, BIIB033, BIIB059, BIIB061, bimekizumab, binimetinib, bleomycin, blinatumomab, BNZ-1, bortezomib (e.g. VELCADE), brentuximab vedotin, bryostatin 1, bucillamine, buparlisib, busulfan, canakinumab, capecitabine, carboplatin, carfilzomib, carmustine, cediranib maleate, cemiplimab, ceralifimod, cerdulatinib, certolizumab (e.g. certolizumab pegol), cetuximab, chidamide, chlorambucil, CHS-131, cilengitide, cirmtuzumab, cisplatin, cladribine, clazakizumab, clemastine, clioquinol, corticosteroids, cyclophosphamide, cyclosporine, cytarabine, cytotoxic chemotherapy, daclizumab, dalfampridine (e.g. AMPYRA), daprolizumab pegol, daratumumab, dasatinib, defactinib, defibrotide, denosumab, dexamethasone, diacerein, dimethyl fumarate, dinaciclib, diroximel fumarate (e.g. VUMERITY), doxorubicin, doxorubicin (e.g. doxorubicin hydrochloride), durvalumab, duvelisib, duvortuxizumab, eculizumab (e.g. SOLIRIS), efalizumab, eftilagimod alpha, EK-12 (a neuropeptide combination of metenkefalin and tridecactide), elezanumab, elotuzumab (e.g. EMPLICITI), encorafenib, enfuvirtida (e.g. FUZEON), entinostat, entospletinib, enzastaurin, epacadostat, epirubicin, epratuzumab, eritoran tetrasodium, etanercept, etoposide, etrolizumab, everolimus, evobrutinib, filgotinib, fingolimod (e.g. fingolimod hydrochloride), firategrast, fludarabine, fluorouracil, fontolizumab, forodesine hydrochloride, fostamatinib, galunisertib, ganetespib, ganitumab, gemcitabine, gemtuzumab ozogamicin, gerilimzumab, glasdegib, glassia, glatiramer acetate, glembatumumab vedotin, glesatinib, golimumab (e.g. SIMPONI), guadecitabine, hydrocortisone, hydroxychloroquine sulfate, hydroxyurea, ibritumomab tiuxetan, ibrutinib, ibudilast, idarubicin, idebenone, idelalisib, ifosfamide, iguratimod, imatinib, imexon, IMU-838, infliximab, inotuzumab ozogamicin, interferon alfa-2, interferon beta-1a, interferon beta-1b, interferon gamma-1, ipilimumab, irofulven, isatuximab, ispinesib, itacitinib, ixazomib, lapatinib, laquinimod, laromustine, ld-aminopterin, leflunomide, lenalidomide, lenvatinib, letrozole (e.g. FEMARA), levamisole, levocabastine, lipoic acid, lirilumab, lonafarnib, lumiliximab, maraviroc (e.g. SELZENTRY), masitinib, mavrilimumab, melphalan, mercaptopurine, methotrexate, methoxsalen, methylprednisone, milatuzumab, mitoxantrone, mizoribine, mocetinostat, monalizumab, mosunetuzumab, motesanib diphosphate, moxetumomab pasudotox, muromonab-CD3, mycophenolate mofetil (e.g. mycophenolate mofetil hydrochloride), mycophenolic acid, namilumab, natalizumab, navitoclax, neihulizumab, nerispirdine, neurovax, niraparib, nivolumab, obatoclax mesylate, obinutuzumab, oblimersen sodium, ocrelizumab, ofatumumab, olokizumab, opicinumab, oprelvekin, osimertinib, otelixizumab, oxaliplatin, oxcarbazepine, ozanimod, paclitaxel, pacritinib, palifermin, panobinostat, pazopanib, peficitinib, pegfilgrastim (e.g. NEULASTA), peginterferon beta-1a, pegsunercept (peg stnf-ri), pembrolizumab, pemetrexed, penclomedine, pentostatin, perifosine, pevonedistat, pexidartinib, picoplatin, pidilizumab, pivanex, pixantrone, pleneva, plovamer acetate, polatuzumab vedotin, pomalidomide, ponatinib, ponesimod, prednisone/prednisolone, pyroxamide, R-411, ravulizimab-cwvz (e.g. (ULTOMIRIS), recombinant il-12, relatlimab, rhigf-1, rhigm22, rigosertib, rilonacept, ritonavir (e.g. NORVIR), rituximab, ruxolitinib, SAR442168/PRN2246, sarilumab, secukinumab, selumetinib, simvastatin, sintilimab, siplizumab, siponimod (e.g. MAYZENT), sirolimus (rapamycin), sirukumab, sitravatinib, sonidegib, sorafenib, sotrastaurin acetate, sunitinib, sunphenon epigallocatechin-gallate, tabalumab, tacrolimus (e.g. tacrolimus anhydrous), talabostat mesylate, talacotuzumab, tanespimycin, tegafur/gimeracil/oteracil, temozolomide, temsirolimus, tenalisib, terameprocol, teriflunomide, thalidomide, thiarabine, thiotepa, tipifarnib, tirabrutinib, tislelizumab, tivozanib, tocilizumab, tofacitinib, TR-14035, tregalizumab, tremelimumab, treosulfan, ublituximab, umbralisib, upadacitinib, urelumab, ustekinumab, varlilumab, vatelizumab, vedolizumab, veliparib, veltuzumab, venetoclax, vinblastine, vincristine, vinorelbine ditartrate, visilizumab, vismodegib, vistusertib, voriconazole (e.g. VFEND), vorinostat, vosaroxin, ziv-aflibercept, 2B3-201, 3PRGD2, 4SC-202, 506U78, 6,8-bis(benzylthio)octanoic acid, 68Ga-BNOTA-PRGD2, 852A, 89Zr-DFO-CZP, ABBV-257, ABL001, ABP 501, ABP 710, ABP 798, ABT-122, ABT-199, ABT-263, ABT-348, ABT-494, ABT-555, ABT-874, ABX-1431 HCl, ACP-196, ACP-319, ACT-128800, ACY-1215, AD 452, Ad-P53, ADCT-301, ADCT-402, ADL5859, ADS-5102, AFX-2, AGEN1884, AGEN2034, AGS67E, AIN457, AK106-001616, ALD518, ALKS 8700, ALT-803, ALT-803, ALX-0061, ALXN1007, ALXN6000, AMD3100, AMG 108, AMG 319, AMG 357, AMG 570, AMG 592, AMG 714, AMG 719, AMG 827, AMP-110, AP1903, APL A12, AP0866, APX005M, AQ4N, AR-42, ARN-6039, ARQ 531, ARRY-371797, ARRY-382, ARRY-438162, ART-I02, ART621, ASK8007, ASNO02, ASP015K, ASP1707, ASP2408, ASP2409, ASP5094, AT-101, AT7519M, AT9283, ATA188, ATN-103, ATX-MS-1467, AVL-292, AVP-923, AZD4573, AZD5672, AZD5991, AZD6244, AZD6738, AZD9056, AZD9150, AZD9567, AZD9668, B-701, BAF312, BAY1830839, BBI608, BCD-054, BCD-055, BCD-063, BCD-089, BCD-100, BCD-132, BCD-145, BEZ235, BG00012, BG9924, BGB-3111, BGB-A333, BGG492, BHT-3009, BI 655064, BI 695500, BI 695501, BI 836826, BI-1206, MBR 796 BS, BIIB017, BIIB023, BIIB057, BIIB061, BIIL 284 BS, BLZ945, BMMNC, BMN 673, BMS-247550, BMS-582949, BMS-817399, BMS-936558, BMS-936564, BMS-945429, BMS-986104, BMS-986142, BMS-986156, BMS-986195, BMS-986205, BMS-986213, BMS-986226, BMS-986251, BNC105P, BOW015, BP1001, BT061, BTT-1023, C105, CAL-101, CAM-3001, CAT-8015, CB-839, CBL0137, CC-1088, CC-115, CC-122, CC-292, CC100, CCI-779, CCX 354-C, CDKI AT7519, CDP323, CDP6038, CDP870, CDX-1127, CDX-301, CE-224535, CF101, CFZ533, CGP 77116, CH-1504, CH-4051, CHR-5154, CHS-0214, CK-2017357, CLAG-M, CLR 131, CMAB008, CMP-001, CNF2024 (BIIB021), CNM-Au8, CNTO 1275, CNTO 136, CNTO 148, CNTO 6785, CP-195543, CP-461, CpG 7909, CPI-1205, CR6086, CRx-102, CS-0777, CS1002, CT-011, CT-1530, CT-P10, CV301, CX-3543, DAC-HYP, DCDT2980S, DI-B4, DPA-714 FDG, DS-3032b, DT2219ARL, DTRM-505, DTRM-555, DTRMWXHS-12, DWP422, E6011, E7449, EK-12, ELND002, ENIA11, EOC202, ETBX-011, F8IL10, FBTA05, FEDAA1106 (BAY85-8101), FGF401, FKB327, FPA008, FR104, FS118, FTY720, G100, GCS-100, GDC-0199, GDC-0853, GEH120714, GLPG0259, GLPG0634, GNbAC1, GNKG168, GP2013, GP2015, GRN163L, GS-1101, GS-5745, GS-9219, GS-9820, GS-9876, GS-9901, GSK1223249, GSK1827771, GSK2018682, GSK21110183, GSK239512, GSK2618960, GSK2831781, GSK2982772, GSK3117391, GSK3152314A, GSK3196165, GSK3358699, GSK706769, GW-1000-02, GW274150, GW406381, GW856553, GZ402668, HCD122, HE3286, HL2351, HL237, hLL1-DOX (IMMU-115), HLX01, HM71224, HMPL-523, HSC835, HZT-501, ICP-022, IDEC-C2B8, ILV-094, IMGN529, IMMU-114, IMO-2125, INCAGN02385, INCB018424, INCB028050, INCB039110, INCB047986, INCMGA00012, INNO-406, INT131, INT230-6, INVAC-1, IPI-145, IPX056, ISF35, ISIS 104838, ITF2357, JCARH125, JHL1101, JNJ 38518168, JNJ-39758979, JNJ-40346527, JNJ-63723283, JS001, JTE-051, JTX-2011, KB003, KD025, KPT-330, KW-2449, KW-2478, KX2-391, L-778123, LAG525, LAM-002A, LBEC0101, LBH589, LFB-R603, LMB-2, LX3305, LY2127399, LY2189102, LY2439821, LY3009104, LY3090106, LY3300054, LY3321367, LY3337641, M2951, M7824, M923, MBG453, MBP8298, MBS2320, MD1003, MDG013, MDV9300, MDX-1100, MDX-1342, MDX-1411, ME-401, MEDI-522, MEDI-538, MEDI-551, MEDI4920, MGA012, MGCD0103, MGD007, MIS416, MK-0873, MK-4280, MK-4827, MK-8457, MK-8808, MK0359, MK0457, MK0752, MK0782, MK0812, MK2206, MLN1202, MLTA3698A, MM-093, MN-122, MN-166, monoclonal antibody M-T412, monoclonal antibody mono-dgA-RFB4, MOR00208, MOR103, MORAb-022, MP-435, MP470, MRC375, MRG-106, MS-533, MSB11022, MSC2490484A, MT-1303, MT-3724, MTIG7192A, MTRX1011A, NBI-5788, NC-503, NI-0101, NI-071, NIS793, NKTR-214, NNC 0141-0000-0100, NNC 0151-0000-0000, NNC0109-0012, NNC0114-0000-0005, NNC0114-0006, NNC0142-0002, NNCO215-0384, NNC109-0012, NOX-A12, NT-KO-003, NU100, OMB157, OMP-313M32, ON01910 Na, ONO-2506P0, ONO-4641, ONTAK, OPB 31121, OSI-461, OTS167IV, P1446A-05, PBF-509, PBRO6, PCI 32765, PCI-24781, PD 0360324, PDA001, PDR001, PF-04171327, PF-04236921, PF-04308515, PF-04629991, PF-05280586, PF-06342674, PF-06410293, PF-06438179, PF-06650833, PF-06651600, PF-06835375, PG-760564, PH-797804, PLA-695, PLX3397, PLX5622, POL6326, PRO131921, PRO283698, PRTX-100, PS-341, PTL201, R(+)XK469, R788, RAD001, RC18, REGN1979, REGN3767, REGN2810, REGN4659, RFT5-SMPT-dgA, RG2077, RGB-03, RGI-2001, RHB-104, RNS60, RO5045337, RO7123520, Rob 803, RPC1063, RWJ-445380, S 55746, SAIT101, SAN-300, SAR245409, SB-681323, SB683699, SBI-087, SC12267 (4SC-101), SCH 727965, SC10-469, SD-101, SG2000, SGN-40, SHC014748M, SHR-1210, SHR0302, SHR1020, SJG-136, SKI-O-703, SMP-114, SNS-032, SNS-062, SNX-5422, SPARC1103 I, SPC2996, SSR150106, STA 5326 mesylate, Sunpharma1505, SyB L-0501, Sym022, Sym023, SYN060, T-614, T0001, TA-650, TAB08, TAK-715, TAK-783, TAK-901, TGR-1202, TH-302, TL011, TMI-005, TMP001, TNFa Kinoid, TP-0903, TRU-015, TRU-016, TSR-022, TSR-033, TSR-042, TXA127, VAY736, VP-16, VSN16R, VX-509, VX-702, VX-745, VX15/2503, XCEL-MC-ALPHA, XL228, XL844, XmAb13676, XmAb5574, XOMA 052, YRA-1909, Z102, ZEN003365 or any combination thereof.

Exemplary small molecule immunosuppressive medications include dimethyl fumarate, fingolimod, diroximel fumarate, and ruxolitinib. In some embodiments, an immunosuppressive therapy is classified as a Class 1 (high risk) therapeutic agent, such as efalizumab and natalizumab as reported in Calabrese L. H. et al., Nat Rev Rheumatol. (2015).

In some cases, the immunosuppressive medications can be DNA and/or RNA crosslinking agents, including alkylating agents, nitrogen mustard alkylating agents, topoisomerase inhibitors, anthracyclines, and platinum-based anticancer drugs. In some cases, the immunosuppressive medications can be kinase inhibitors, including phosphoinositide-3-kinase, cyclin-dependent kinase (e.g., CDK9), Aurora kinase, ROCK, Akt, or PKC. In some cases, the immunosuppressive medications can be tyrosine kinase inhibitors, including inhibitors of the fusion protein breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL), Bruton's tyrosine kinase (BTK), epidermal growth factor receptor (EGFR), Janus kinase (JAK), Syk, Lyn, MEK, FAK, BRAF, AXL, or vascular endothelial growth factor (VEGF). In some cases, the immunosuppressive medications can be monoclonal antibodies and/or antibody-drug conjugates directed at proteins including cluster of differentiation (CD) proteins, such as CD2, CD3, CD11a, CD20, CD30, CD52, CD-19, CD-38, CD-26, CD-37, CD-22, CD-33, CD-23, CD-74, CD-162, CD-79, CD-123, CD-4, CD-137, CD-27, CD-36, CD-39, CD-73, CD-226, CD-155, CD-40; interleukins (IL), such as IL-1, IL-2, IL-6, IL-12, IL-23; tumor necrosis factor (TNF) family proteins, such as TNFa; and integrins, such as integrin α4, α_(v)β₃, α_(v)β₅, α_(v)β₃, or α₂. In some cases, the immunosuppressive medications can be monoclonal antibodies and/or antibody-drug conjugates directed at Programmed cell death receptor 1 (PD-1), Programmed cell death ligand 1 (PD-L1), Cytotoxic T-lymphocyte associated protein 4 (CTLA-4), Lymphocyte activation gene 3 (LAG-3), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), also known as WUCAM or Vstm3, B and T lymphocyte attenuator (BTLA), Glucocorticoid-induced TNFR family related gene (GITR), OX40, HSP90, killer-cell immunoglobulin-like receptor (KIR), Toll-like receptor 9 (TLR9), Toll-like receptor 4 (TLR4), Matrix metallopeptidase 9 (MMP), Interferon receptor, Interferon gamma, Transforming growth factor 1b (TGF1β), Insulin growth factor 1 receptor (IGF1 R), Fibroblast growth factor receptor (FGFrR3, FGFR4), Neuromedin B, Granulocyte-macrophage colony stimulating factor receptor (GM-CSF R), Natural killer cell receptor (NKG-2a), Leucine rich repeat and Immunoglobin-like domain-containing protein 1 (LINGO1), B-cell activating factor (BAFF), Inducible T-cell co-stimulator (ICOS). In some cases, the monoclonal antibody/antibody-drug conjugate can activate the target.

In some cases, the monoclonal antibody/antibody-drug conjugate can inhibit the target. In some cases, the immunosuppressive medications can be inhibitors of RANKL (receptor activator of nuclear factor kappa-B ligand). In some cases, the immunosuppressive medications can be inhibitors of histone deacetylase (HDAC). In some cases, the immunosuppressive medications can be inhibitors of heat shock protein 90 (HSP90). In some cases, the immunosuppressive medications can be inhibitors of cytidine deaminase (CDA). In some cases, the immunosuppressive medications can be inhibitors of Hedgehog signaling pathway (including Sonic hedgehog and Smoothened). In some cases, the immunosuppressive medications can be inhibitors of alpha-1-proteinase. In some cases, the immunosuppressive medications can be inhibitors of cyclooxygenase 2 (COX2). In some cases, the immunosuppressive medications can be inhibitors of complement (C5a). In some cases, the immunosuppressive medications can be inhibitors of colony stimulating factor 1 receptor (CSF1R). In some cases, the immunosuppressive medications can be inhibitors of Notch. In some cases, the immunosuppressive medications can be inhibitors of kinesin. In some cases, the immunosuppressive medications can be inhibitors of farnesyltransferase. In some cases, the immunosuppressive medications can be inhibitors of poly(ADP-ribose) polymerase (PARP). In some cases, the immunosuppressive medications can be inhibitors of Neural Precursor Cell Expressed, Developmentally Down-Regulated (NEDD8). In some cases, the immunosuppressive medications can be inhibitors of dipeptidyl peptidase IV (DPP-IV). In some cases, the immunosuppressive medications can be inhibitors of leucine-rich repeat kinase 2 (LRRK2). In some cases, the immunosuppressive medications can be inhibitors of immune checkpoint proteins. In some cases, the immunosuppressive medications can be inhibitors of indoleamine 2,3-dioxygenase-1 (IDO1). In some cases, the immunosuppressive medications can be inhibitors of chemokine receptors (CCR4, CCR5, CCR7). In some cases, the immunosuppressive medications can be immunosuppression-inducing therapies such as T-cells or regulatory T-cells modified with a chimeric antigen receptor (CAR-T, CAR-Tregs). In some cases, the immunosuppressive medications can be structured lipids. In some cases, the immunosuppressive medications can be Ras mimetic. In some cases, the immunosuppressive medications can be inhibitors of NOD-like receptor pyrin domain-containing protein 3 (NLRP3). In some cases, the immunosuppressive medications can be mTOR and/or calcineurin inhibitors. In some cases, the immunosuppressive medications can be complement inhibitors. In some cases, the immunosuppressive medications can be immunosuppressive antimetabolites, nucleoside metabolic inhibitors, imidazole nucleosides, nucleotide analogs, nucleoside synthesis inhibitors, purine synthesis inhibitors, pyrimidine synthesis inhibitors, or pyrimidine synthase inhibitors. In some cases, the immunosuppressive medications can be recombinant proteins, such as recombinant interferon beta, IL-2, IL-11, Lymphotoxin B fusion protein, Therapeutic T cell receptor peptide vaccine, Keratinocyte growth factor, or Tumor necrosis factor (TNF) receptor.

In some cases, the immunosuppressive medications can be sphingosine-1-phosphate receptor and/or nicotinic acetylcholine receptor modulators. For example, siponimod (BAF312) can be used for the treatment of secondary progressive MS (Kappos L et al. 2018, PMID 29576505). Another medication, ibudilast (MN-122), can be used for the treatment of progressive MS (Fox R et al. 2016, PMID 27521810). In some cases, the immunosuppressive medications can be therapeutic antibodies, including Immunoglobulin G. In some cases, the immunosuppressive medications can be asparaginase inhibitors. In some cases, the immunosuppressive medications can be B-lymphocyte stimulator (BLyS)-specific inhibitor. In some cases, the immunosuppressive medications can be T-cell costimulation modulators. In some cases, the immunosuppressive medications can be cyclic polypeptide immunosuppressants and/or synthetic polypeptides that modify immune processes. In some cases, the immunosuppressive medications can be corticosteroids. In some cases, the immunosuppressive medications can be cytotoxic chemotherapy drugs. In some cases, the immunosuppressive medications can be cytotoxic glycopeptide antibiotics and/or mixtures thereof. In some cases, the immunosuppressive medications can be molecules that inhibit pro-inflammatory cytokine production. In some cases, the immunosuppressive medications can be thalidomide analogues.

In some cases, the immunosuppressive medication can be a Complement C5a inhibitor. In some cases the immunosuppressive medication can be a CD40 agonist. In some cases, the immunosuppressive medication can be a p38 inhibitor. In some cases, the immunosuppressive medication can be a CSF1R inhibitor. In some cases, the immunosuppressive medication can be a MEK inhibitor. In some cases, the immunosuppressive medication can be a neutrophil elastase inhibitor. In some cases, the immunosuppressive medication can be FGFrR3 inhibitor. In some cases, the immunosuppressive medication can be anti-LAG3 mAb, Anti-CXCR, glucocorticoid-induced tumor necrosis factor receptor-related gene [GITR] agonist, IDO1 inhibitor, ICOS agonist, glutaminase inhibitor, recombinant human Flt3L, TLR9 agonist, EZH2 inhibitor, anti-CTLA4 mAb, PD-1 inhibitor, PD-L1 inhibitor, anti-PD-L1 mAb, FGFR4 inhibitor, bispecific anti-PD-1 and anti-LAG3 mAb, TLR4 agonist, Bcl-2 Inhibitor, or anti-LAG3 mAb. In some cases, the immunosuppressive medications can be inhibitors of cell degradation pathways, such as proteasome inhibitors. In some cases, the immunosupressive medication can be selected from A2aR antagonist, Akt inhibitor, anti CD20, Anti-amyloidotic (AA) Agent, anti-CD37 protein therapeutic, anti-CTLA4 mAb, Anti-CXCR4, anti-huCD40 mAb, anti-LAG3 mAb, anti-PD-1 mAb, anti-PD-L1 agent, anti-PD-L1 agent, anti-PD-L1 mAb, anti-TGFb mAb, anti-TIGIT mAb, anti-TIM-3 mAb, Aurora kinase inhibitor, Bcl-2 Inhibitor, bifunctional fusion protein targeting TGFb and PD-L1, bispecific anti-PD-1 and anti-LAG3 mAb, CD1d ligand, CD40 agonist, Complement C5a inhibitor, CSF1R inhibitor, EZH2 inhibitor, FGFR3 inhibitor, FGFR4 inhibitor, FGFrR3 inhibitor, glucocorticoid-induced tumor necrosis factor receptor-related gene [GITR] agonist, glutaminase inhibitor, Human monoclonal antibody against IL-12, ICOS agonist, IDO1 inhibitor, IL2 mutein, IL2 receptor agonist, MEK inhibitor, multitargeted receptor tyrosine kinase inhibitor, neutrophil elastase inhibitor, Notch Inhibitor, p38 MAPK inhibitor, PD-1 inhibitor, recombinant human Flt3L, ROCK inhibitor, selective sphingosine-1-phosphate receptor modulator, Src kinase inhibitor, TLR4 agonist, TLR9 agonist.

In some cases, the immunosupressive medication can be selected from 2B3-201, 3PRGD2, 4SC-202, 506U78, 6,8-bis(benzylthio)octanoic acid, 68Ga-BNOTA-PRGD2, 852A, 89Zr-DFO-CZP, ABBV-257, ABL001, ABP 501, ABP 710, ABP 798, ABT-122, ABT-199, ABT-263, ABT-348, ABT-494, ABT-555, ABT-874, ABX-1431 HCl, ACP-196, ACP-319, ACT-128800, ACY-1215, AD 452, Ad-P53, ADCT-301, ADCT-402, ADL5859, ADS-5102, AFX-2, AGEN1884, AGEN2034, AGS67E, AIN457, AK106-001616, ALD518, ALKS 8700, ALT-803, ALT-803, ALX-0061, ALXN1007, ALXN6000, AMD3100, AMG 108, AMG 319, AMG 357, AMG 570, AMG 592, AMG 714, AMG 719, AMG 827, AMP-110, AP1903, APL A12, AP0866, APX005M, AQ4N, AR-42, ARN-6039, ARQ 531, ARRY-371797, ARRY-382, ARRY-438162, ART-I02, ART621, ASK8007, ASNO02, ASP015K, ASP1707, ASP2408, ASP2409, ASP5094, AT-101, AT7519M, AT9283, ATA188, ATN-103, ATX-MS-1467, AVL-292, AVP-923, AZD4573, AZD5672, AZD5991, AZD6244, AZD6738, AZD9056, AZD9150, AZD9567, AZD9668, B-701, BAF312, BAY1830839, BBI608, BCD-054, BCD-055, BCD-063, BCD-089, BCD-100, BCD-132, BCD-145, BEZ235, BG00012, BG9924, BGB-3111, BGB-A333, BGG492, BHT-3009, BI 655064, BI 695500, BI 695501, BI 836826, BI-1206, MBR 796 BS, BIIB017, BIIB023, BIIB057, BIIB061, BIIL 284 BS, BLZ945, BMMNC, BMN 673, BMS-247550, BMS-582949, BMS-817399, BMS-936558, BMS-936564, BMS-945429, BMS-986104, BMS-986142, BMS-986156, BMS-986195, BMS-986205, BMS-986213, BMS-986226, BMS-986251, BNC105P, BOW015, BP1001, BT061, BTT-1023, C105, CAL-101, CAM-3001, CAT-8015, CB-839, CBL0137, CC-1088, CC-115, CC-122, CC-292, CC100, CCI-779, CCX 354-C, CDKI AT7519, CDP323, CDP6038, CDP870, CDX-1127, CDX-301, CE-224535, CF101, CFZ533, CGP 77116, CH-1504, CH-4051, CHR-5154, CHS-0214, CK-2017357, CLAG-M, CLR 131, CMAB008, CMP-001, CNF2024 (BIIB021), CNM-Au8, CNTO 1275, CNTO 136, CNTO 148, CNTO 6785, CP-195543, CP-461, CpG 7909, CPI-1205, CR6086, CRx-102, CS-0777, CS1002, CT-011, CT-1530, CT-P10, CV301, CX-3543, DAC-HYP, DCDT2980S, DI-B4, DPA-714 FDG, DS-3032b, DT2219ARL, DTRM-505, DTRM-555, DTRMWXHS-12, DWP422, E6011, E7449, EK-12, ELND002, ENIA11, EOC202, ETBX-011, F8IL10, FBTA05, FEDAA1106 (BAY85-8101), FGF401, FKB327, FPA008, FR104, FS118, FTY720, G100, GCS-100, GDC-0199, GDC-0853, GEH120714, GLPG0259, GLPG0634, GNbAC1, GNKG168, GP2013, GP2015, GRN163L, GS-1101, GS-5745, GS-9219, GS-9820, GS-9876, GS-9901, GSK1223249, GSK1827771, GSK2018682, GSK21110183, GSK239512, GSK2618960, GSK2831781, GSK2982772, GSK3117391, GSK3152314A, GSK3196165, GSK3358699, GSK706769, GW-1000-02, GW274150, GW406381, GW856553, GZ402668, HCD122, HE3286, HL2351, HL237, hLL1-DOX (IMMU-115), HLX01, HM71224, HMPL-523, HSC835, HZT-501, ICP-022, IDEC-C2B8, ILV-094, IMGN529, IMMU-114, IMO-2125, INCAGN02385, INCB018424, INCB028050, INCB039110, INCB047986, INCMGA00012, INNO-406, INT131, INT230-6, INVAC-1, IPI-145, IPX056, ISF35, ISIS 104838, ITF2357, JCARH125, JHL1101, JNJ 38518168, JNJ-39758979, JNJ-40346527, JNJ-63723283, JS001, JTE-051, JTX-2011, KB003, KD025, KPT-330, KW-2449, KW-2478, KX2-391, L-778123, LAG525, LAM-002A, LBEC0101, LBH589, LFB-R603, LMB-2, LX3305, LY2127399, LY2189102, LY2439821, LY3009104, LY3090106, LY3300054, LY3321367, LY3337641, M2951, M7824, M923, MBG453, MBP8298, MBS2320, MD1003, MDG013, MDV9300, MDX-1100, MDX-1342, MDX-1411, ME-401, MEDI-522, MEDI-538, MEDI-551, MEDI4920, MGA012, MGCD0103, MGD007, MIS416, MK-0873, MK-4280, MK-4827, MK-8457, MK-8808, MK0359, MK0457, MK0752, MK0782, MK0812, MK2206, MLN1202, MLTA3698A, MM-093, MN-122, MN-166, monoclonal antibody M-T412, monoclonal antibody mono-dgA-RFB4, MOR00208, MOR103, MORAb-022, MP-435, MP470, MRC375, MRG-106, MS-533, MSB11022, MSC2490484A, MT-1303, MT-3724, MTIG7192A, MTRX1011A, NBI-5788, NC-503, NI-0101, NI-071, NIS793, NKTR-214, NNC 0141-0000-0100, NNC 0151-0000-0000, NNC0109-0012, NNC0114-0000-0005, NNC0114-0006, NNC0142-0002, NNCO215-0384, NNC109-0012, NOX-A12, NT-KO-003, NU100, OMB157, OMP-313M32, ON01910 Na, ONO-2506P0, ONO-4641, ONTAK, OPB 31121, OSI-461, OTS167IV, P1446A-05, PBF-509, PBRO6, PCI 32765, PCI-24781, PD 0360324, PDA001, PDR001, PF-04171327, PF-04236921, PF-04308515, PF-04629991, PF-05280586, PF-06342674, PF-06410293, PF-06438179, PF-06650833, PF-06651600, PF-06835375, PG-760564, PH-797804, PLA-695, PLX3397, PLX5622, POL6326, PRO131921, PRO283698, PRTX-100, PS-341, PTL201, R(+)XK469, R788, RAD001, RC18, REGN1979, REGN3767, REGN2810, REGN4659, RFT5-SMPT-dgA, RG2077, RGB-03, RGI-2001, RHB-104, RNS60, RO5045337, RO7123520, Rob 803, RPC1063, RWJ-445380, S 55746, SAIT101, SAN-300, SAR245409, SB-681323, SB683699, SBI-087, SC12267 (4SC-101), SCH 727965, SCIO-469, SD-101, SG2000, SGN-40, SHC014748M, SHR-1210, SHR0302, SHR1020, SJG-136, SKI-O-703, SMP-114, SNS-032, SNS-062, SNX-5422, SPARC1103 I, SPC2996, SSR150106, STA 5326 mesylate, Sunpharma1505, SyB L-0501, Sym022, Sym023, SYN060, T-614, T0001, TA-650, TAB08, TAK-715, TAK-783, TAK-901, TGR-1202, TH-302, TL011, TMI-005, TMP001, TNFa Kinoid, TP-0903, TRU-015, TRU-016, TSR-022, TSR-033, TSR-042, TXA127, VAY736, VP-16, VSN16R, VX-509, VX-702, VX-745, VX15/2503, XCEL-MC-ALPHA, XL228, XL844, XmAb13676, XmAb5574, XOMA 052, YRA-1909, Z102, ZEN003365.

PML can be diagnosed in a patient with a progressive course of the disease, finding JC virus DNA in spinal fluid together with consistent white matter lesions on brain magnetic resonance imaging (MRI); alternatively, a brain biopsy can be diagnostic when the typical histopathology of demyelination, bizarre astrocytes, and enlarged oligodendroglial nuclei are present, coupled with techniques showing the presence of JC virus. Characteristic evidence of PML on brain CT scan images can be multifocal, non-contrast enhancing hypodense lesions without mass effect, but MRI can be more sensitive than CT. The most common area of involvement can be the cortical white matter of frontal and parieto-occipital lobes, but lesions may occur anywhere in the brain, like the basal ganglia, external capsule, and posterior cranial fossa structures like the brainstem and cerebellum.

In general, treatment of PML aims at reversing the immune deficiency to slow or stop the disease progress. Patients on an immunosuppression regime can stop taking the immunosuppressive medication or plasma exchange (PLEX) can be used to accelerate the removal of the immunosuppressive medication that put the person at risk for PML. HIV-infected patients can start highly active antiretroviral therapy (HAART). Occurrence of PML can also occur in the context of immune reconstitution inflammatory syndrome (IRIS), wherein onset of PML can occur or PML symptoms may get worse after cessation of immunosuppression (e.g., as reviewed by Pavlovic et al. Ther Adv Neurol Disord. 2015 November; 8(6):255-73 and Bowen et al. Nat Rev Neurol. 2016 Oct. 27; 12(11):662-674). For example, in MS patients that develop PML during treatment with natalizumab, IRIS often results when treatment is stopped and PLEX is used to remove natalizumab from the patient's circulation. Treatment of IRIS in PML patients can include administration of corticosteroids. Other potential treatments of PML can include cidofovir, cytarabine, anti-malaria drug mefloquine, interleukin-2, and 1-O-hexadecyloxypropyl-cidofovir (CMX001, aka brincidofovir). As reviewed by Pavlovic (Ther Adv Neurol Disord. 2015 November; 8(6):255-73), potential treatments for PML include antiviral agents (e.g., chlorpromazine, citalopram, mirtazapine, risperidone, ziprasidone, retro-2cycl, brefeldin A, cidofovir, brincidofovir, cytarabine, ganciclovir, leflunomide, topotecan, mefloquine, 3-aminobenzamide, imatinib, and Ag122), immune response modulators (e.g., IFN-alpha, IL-2, IL-7, maraviroc, and glucocorticoids), and immunization (e.g., recombinant human anti-JCV VP-1 monoclonal antibodies, JCV-specific cytotoxic T lymphocyte therapy, IL-7 plus JCV VP1 vaccine, and JCV oral vaccine).

The term “diagnostic yield” as used herein refers to the percentage of cases that would identify the presence of one or more genetic variations (e.g., CNV, SNV) in a PML cohort using an assay. For example, if 40 cases would identify the presence of one or more genetic variations (e.g., CNV, SNV) in a cohort of 100 PML patients, the diagnostic yield of the assay is 40%. In some cases, the patients in the PML cohort are clinically diagnosed with PML. In some cases, a patient is clinically diagnosed with PML when JC virus DNA is present in spinal fluid and consistent white matter lesions is present on brain magnetic resonance imaging (MRI). In some cases, a patient is clinically diagnosed with PML when typical histopathology of demyelination, bizarre astrocytes, and enlarged oligodendroglial nuclei are present in a brain biopsy, coupled with the presence of JC virus. In some cases, the PML cohort has at least 5 PML cases, for example, at least 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 PML cases. In some cases, the PML cohort is a cohort listed herein. For example, the PML cohort is the PML patient cohort listed in Table 7. In some cases, the assay is JCV-antibody assay. In some cases, the assay is not JCV-antibody assay. In some cases, the assay is a genetic assay. In some cases, the genetic assay tests the genetic predisposition for PML.

The genetic assay can comprise any method disclosed herein. In some cases, the genetic assay has a diagnostic yield of at least about 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%. In some cases, the genetic assay has a diagnostic yield of about 1%-5%, 1%-10%, 1%-20%, 5%-10%, 5%-20%, 10%-20%, 10%-30%, 20%-30%, 20%-40%, 30%-40%, 30%-50%, 40%-50%, 40%-60%, 50%-60%, 50%-70%, 60%-70%, 60%-80%, 70%-80%, 70%-90%, 80%-90%, 80%-95%, 90%-95%, 90%-99%, 90%-100%, 95%-99%, or 99%-100%.

Genetic Variations Associated with PML

Described herein, are methods that can be used to detect genetic variations. Detecting specific genetic variations, for example polymorphic markers and/or haplotypes, copy number, absence or presence of an allele, or genotype associated with a condition (e.g., disease or disorder) as described herein, can be accomplished by methods known in the art for analyzing nucleic acids and/or detecting sequences at polymorphic or genetically variable sites, for example, amplification techniques, hybridization techniques, sequencing, microarrays/arrays, or any combination thereof. Thus, by use of these methods disclosed herein or other methods available to the person skilled in the art, one or more alleles at polymorphic markers, including microsatellites, single nucleotide polymorphisms (SNPs), single nucleotide variations (SNVs), insertions/deletions (indels), copy number variations (CNVs), or other types of genetic variations, can be identified in a sample obtained from a subject.

Genomic sequences within populations exhibit variability between individuals at many locations in the genome. For example, the human genome exhibits sequence variations that occur on average every 500 base pairs. Such genetic variations in polynucleic acid sequences are commonly referred to as polymorphisms or polymorphic sites. As used herein, a polymorphism, e.g., genetic variation, includes a variation in the sequence of the genome amongst a population, such as allelic variations and other variations that arise or are observed. Thus, a polymorphism refers to the occurrence of two or more genetically determined alternative sequences or alleles in a population. These differences can occur in coding (e.g., exonic) and non-coding (e.g., intronic or intergenic) portions of the genome, and can be manifested or detected as differences in polynucleic acid sequences, gene expression, including, for example transcription, processing, translation, transport, protein processing, trafficking, DNA synthesis; expressed proteins, other gene products or products of biochemical pathways or in post-translational modifications and any other differences manifested amongst members of a population. Polymorphisms that arise as the result of a single base change, such as single nucleotide polymorphisms (SNPs) or single nucleotide variations (SNVs), can include an insertion, deletion or change in one nucleotide. A polymorphic marker or site is the locus at which divergence occurs. Such sites can be as small as one base pair (an SNP or SNV). Polymorphic markers include, but are not limited to, restriction fragment length polymorphisms (RFLPs), variable number of tandem repeats (VNTRs), hypervariable regions, minisatellites, dinucleotide repeats, trinucleotide repeats, tetranucleotide repeats and other repeating patterns, simple sequence repeats and insertional elements, such as Alu. Polymorphic forms also are manifested as different mendelian alleles for a gene. Polymorphisms can be observed by differences in proteins, protein modifications, RNA expression modification, DNA and RNA methylation, regulatory factors that alter gene expression and DNA replication, and any other manifestation of alterations in genomic polynucleic acid or organelle polynucleic acids. Those skilled in the art can appreciate that polymorphisms are sometimes considered to be a subclass of variations, defined on the basis of a particular frequency cutoff in a population. For example, in some embodiments, polymorphisms are considered to genetic variants/variations that occur at >1%, or >5%, frequency in the population.

In some embodiments, these genetic variations can be found to be associated with one or more disorders and/or diseases using the methods disclosed herein. In some embodiments, these genetic variations can be found to be associated with absence of one or more disorders and/or diseases (e.g. the one or more variants are protective against development of the disorder and/or diseases) using the methods disclosed herein.

In some embodiments, these genetic variations comprise point mutations, polymorphisms, single nucleotide polymorphisms (SNPs), single nucleotide variations (SNVs), translocations, insertions, deletions, amplifications, inversions, interstitial deletions, copy number variations (CNVs), structural variation (SV), loss of heterozygosity, or any combination thereof. As genetic variation includes any deletion, insertion or base substitution of the genomic DNA of one or more individuals in a first portion of a total population which thereby results in a difference at the site of the deletion, insertion or base substitution relative to one or more individuals in a second portion of the total population. Thus, the term “genetic variation” encompasses “wild type” or the most frequently occurring variation, and also includes “mutant,” or the less frequently occurring variation. In some embodiments, a wild type allele may be referred to as an ancestral allele.

As used herein, a target molecule that is “associated with” or “correlates with” a particular genetic variation is a molecule that can be functionally distinguished in its structure, activity, concentration, compartmentalization, degradation, secretion, and the like, as a result of such genetic variation. In some embodiments polymorphisms (e.g., polymorphic markers, genetic variations, or genetic variants) can comprise any nucleotide position at which two or more sequences are possible in a subject population. In some embodiments, each version of a nucleotide sequence, with respect to the polymorphism/variation, can represent a specific allele of the polymorphism/variation. In some embodiments, genomic DNA from a subject can contain two alleles for any given polymorphic marker, representative of each copy of the marker on each chromosome. In some embodiments, an allele can be a nucleotide sequence of a given location on a chromosome. Polymorphisms/variations can comprise any number of specific alleles. In some embodiments of the disclosure, a polymorphism/variation can be characterized by the presence of two or more alleles in a population. In some embodiments, the polymorphism/variation can be characterized by the presence of three or more alleles. In some embodiments, the polymorphism/variation can be characterized by four or more alleles, five or more alleles, six or more alleles, seven or more alleles, nine or more alleles, or ten or more alleles. In some embodiments an allele can be associated with one or more diseases or disorders, for example, a PML risk allele can be an allele that is associated with increased or decreased risk of developing PML. In some embodiments, genetic variations and alleles can be used to associate an inherited phenotype with a responsible genotype. In some embodiments, a PML risk allele can be a variant allele that is statistically associated with a screening of PML. In some embodiments, genetic variations can be of any measurable frequency in the population, for example, a frequency higher than 10%, a frequency from 5-10%, a frequency from 1-5%, a frequency from 0.1-1%, or a frequency below 0.1%. As used herein, variant alleles can be alleles that differ from a reference allele. As used herein, a variant can be a segment of DNA that differs from the reference DNA, such as a genetic variation. In some embodiments, genetic variations can be used to track the inheritance of a gene that has not yet been identified, but whose approximate location is known.

As used herein, a “haplotype” can be information regarding the presence or absence of one or more genetic markers in a given chromosomal region in a subject. In some embodiments, a haplotype can be a segment of DNA characterized by one or more alleles arranged along the segment, for example, a haplotype can comprise one member of the pair of alleles for each genetic variation or locus. In some embodiments, the haplotype can comprise two or more alleles, three or more alleles, four or more alleles, five or more alleles, or any combination thereof, wherein, each allele can comprise one or more genetic variations along the segment.

In some embodiments, a genetic variation can be a functional aberration that can alter gene function, gene expression, polypeptide expression, polypeptide function, or any combination thereof. In some embodiments, a genetic variation can be a loss-of-function mutation, gain-of-function mutation, dominant negative mutation, or reversion. In some embodiments, a genetic variation can be part of a gene's coding region or regulatory region. Regulatory regions can control gene expression and thus polypeptide expression. In some embodiments, a regulatory region can be a segment of DNA wherein regulatory polypeptides, for example, transcription or splicing factors, can bind. In some embodiments a regulatory region can be positioned near the gene being regulated, for example, positions upstream or downstream of the gene being regulated. In some embodiments, a regulatory region (e.g., enhancer element) can be several thousands of base pairs upstream or downstream of a gene.

In some embodiments, variants can include changes that affect a polypeptide, such as a change in expression level, sequence, function, localization, binding partners, or any combination thereof. In some embodiments, a genetic variation can be a frameshift mutation, nonsense mutation, missense mutation, neutral mutation, or silent mutation. For example, sequence differences, when compared to a reference nucleotide sequence, can include the insertion or deletion of a single nucleotide, or of more than one nucleotide, resulting in a frame shift; the change of at least one nucleotide, resulting in a change in the encoded amino acid; the change of at least one nucleotide, resulting in the generation of a premature stop codon; the deletion of several nucleotides, resulting in a deletion of one or more amino acids encoded by the nucleotides; the insertion of one or several nucleotides, such as by unequal recombination or gene conversion, resulting in an interruption of the coding sequence of a reading frame; duplication of all or a part of a sequence; transposition; or a rearrangement of a nucleotide sequence. Such sequence changes can alter the polypeptide encoded by the nucleic acid, for example, if the change in the nucleic acid sequence causes a frame shift, the frame shift can result in a change in the encoded amino acids, and/or can result in the generation of a premature stop codon, causing generation of a truncated polypeptide. In some embodiments, a genetic variation associated with PML can be a synonymous change in one or more nucleotides, for example, a change that does not result in a change in the amino acid sequence. Such a polymorphism can, for example, alter splice sites, affect the stability or transport of mRNA, or otherwise affect the transcription or translation of an encoded polypeptide. In some embodiments, a synonymous mutation can result in the polypeptide product having an altered structure due to rare codon usage that impacts polypeptide folding during translation, which in some cases may alter its function and/or drug binding properties if it is a drug target. In some embodiments, the changes that can alter DNA increase the possibility that structural changes, such as amplifications or deletions, occur at the somatic level. A polypeptide encoded by the reference nucleotide sequence can be a reference polypeptide with a particular reference amino acid sequence, and polypeptides encoded by variant nucleotide sequences can be variant polypeptides with variant amino acid sequences.

The most common sequence variants comprise base variations at a single base position in the genome, and such sequence variants, or polymorphisms, are commonly called single nucleotide polymorphisms (SNPs) or single nucleotide variants (SNVs). In some embodiments, a SNP represents a genetic variant present at greater than or equal to 1% occurrence in a population and in some embodiments a SNP or an SNV can represent a genetic variant present at any frequency level in a population. A SNP can be a nucleotide sequence variation occurring when a single nucleotide at a location in the genome differs between members of a species or between paired chromosomes in a subject. SNPs can include variants of a single nucleotide, for example, at a given nucleotide position, some subjects can have a ‘G’, while others can have a ‘C’. SNPs can occur in a single mutational event, and therefore there can be two possible alleles possible at each SNP site; the original allele and the mutated allele. SNPs that are found to have two different bases in a single nucleotide position are referred to as biallelic SNPs, those with three are referred to as triallelic, and those with all four bases represented in the population are quadallelic. In some embodiments, SNPs can be considered neutral. In some embodiments SNPs can affect susceptibility to a condition (e.g., PML). SNP polymorphisms can have two alleles, for example, a subject can be homozygous for one allele of the polymorphism wherein both chromosomal copies of the individual have the same nucleotide at the SNP location, or a subject can be heterozygous wherein the two sister chromosomes of the subject contain different nucleotides. The SNP nomenclature as reported herein is the official Reference SNP (rs) ID identification tag as assigned to each unique SNP by the National Center for Biotechnological Information (NCBI).

Another genetic variation of the disclosure can be copy number variations (CNVs). As used herein, “CNVs” include alterations of the DNA of a genome that results in an abnormal number of copies of one or more sections of DNA. In some embodiments, a CNV comprises a CNV-subregion. As used herein, a “CNV-subregion” includes a continuous nucleotide sequence within a CNV. In some embodiments, the nucleotide sequence of a CNV-subregion can be shorter than the nucleotide sequence of the CNV, and in another embodiment the CNV-subregion can be equivalent to the CNV (e.g., such as for some CNVs). CNVs can be inherited or caused by de novo mutation and can be responsible for a substantial amount of human phenotypic variability, behavioral traits, and disease susceptibility. In some embodiments, CNVs of the current disclosure can be associated with susceptibility to one or more conditions, for example, PML. In some embodiments, CNVs can include a single gene or include a contiguous set of genes. In some embodiments, CNVs can be caused by structural rearrangements of the genome, for example, unbalanced translocations or inversions, insertions, deletions, amplifications, and interstitial deletions. In some embodiments, these structural rearrangements occur on one or more chromosomes. Low copy repeats (LCRs), which are region-specific repeat sequences (also known as segmental duplications), can be susceptible to these structural rearrangements, resulting in CNVs. Factors such as size, orientation, percentage similarity and the distance between the copies can influence the susceptibility of LCRs to genomic rearrangement. In addition, rearrangements may be mediated by the presence of high copy number repeats, such as long interspersed elements (LINEs) and short interspersed elements (SINEs), often via non-homologous recombination. For example, chromosomal rearrangements can arise from non-allelic homologous recombination during meiosis or via a replication-based mechanism such as fork stalling and template switching (FoSTeS) (Zhang F. et al., Nat. Genet. (2009) or microhomology-mediated break-induced repair (MMBIR) (Hastings P. J. et al., PLoS Genetics (2009). In some embodiments, CNVs are referred to as structural variants, which are a broader class of variant that also includes copy number neutral alterations such as balanced inversions and balanced translocations.

CNVs can account for genetic variation affecting a substantial proportion of the human genome, for example, known CNVs can cover over 15% of the human genome sequence (Estivill and Armengol, PLoS Genetics (2007)). CNVs can affect gene expression, phenotypic variation and adaptation by disrupting or impairing gene dosage, and can cause disease, for example, microdeletion and microduplication disorders, and can confer susceptibility to diseases and disorders. Updated information about the location, type, and size of known CNVs can be found in one or more databases, for example, the Database of Genomic Variants (See, MacDonald J R et al., Nucleic Acids Res., 42, D986-92 (2014), which currently contains data for over 500,000 CNVs (as of May, 2016).

Other types of sequence variants can be found in the human genome and can be associated with a disease or disorder, including but not limited to, microsatellites. Microsatellite markers are stable, polymorphic, easily analyzed, and can occur regularly throughout the genome, making them especially suitable for genetic analysis. A polymorphic microsatellite can comprise multiple small repeats of bases, for example, CA repeats, at a particular site wherein the number of repeat lengths varies in a population. In some embodiments, microsatellites, for example, variable number of tandem repeats (VNTRs), can be short segments of DNA that have one or more repeated sequences, for example, about 2 to 5 nucleotides long, that can occur in non-coding DNA. In some embodiments, changes in microsatellites can occur during genetic recombination of sexual reproduction, increasing or decreasing the number of repeats found at an allele, or changing allele length.

The genetic variations disclosed herein can be associated with a risk of developing PML in a subject. In some cases, the subject can have a decreased risk due to the absence of one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 1 to 26. For example, the subject can have a decreased risk due to the absence of one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3 and 6. In some cases, the subject can have an increased risk due to the presence of one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 1 to 26. For example, the subject can have an increased risk due to the presence of one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3 and 6. In some cases, one or more genes listed in Tables 25A, 25B, and 26 can be removed from any one of the Tables 1-24. In some cases, one or more genes listed in Tables 25A, 25B, and 26 can be added to any one of the Tables 1-24.

TABLE 25A Exemplary 8-gene panel Gene RefSeq Num- Gene Disease Gene ber Symbol Model Source Source Annotation (GN) BAG3 AR Public db PMID: 19229298, 19282432, 175 22984599, 27042682 BTK XLR Public db PMID: 18281276, 23765059, 180 25930993, 26029204 CD40LG XLR Public db PMID: 17360404, 21455173, 206 23765059, 26008899, 26029204 DOCK8 AR Public db PMID: 23765059, 23887241, 242 26029204, 26454313 MAGT1 XLR Public db PMID: 23887241, 25504528, 326 27873163 RAG1 AD AR Public db PMID: 23122631, 23765059, 370 23887241, 25976673, 26029204, 26454313, 27484032, 27808398 STAT1 AD AR Public db PMID: 23887241, 25645939, 436 26029204, 26513235, 26743090, 27821552, 27873163 WAS XLR Both PMID: 12874226, 14647476, 483 19782549, 20008220, 24753205, 26029204, 26371186

TABLE 25B Exemplary 16-gene panel Gene RefSeq Num- Gene Disease Gene ber Symbol Model Source Source Annotation (GN) ADA AR Both PMID: 23765059, 24135998, 1 25930993, 26029204, 26454313 BAG3 AR Public db PMID: 19229298, 19282432, 175 22984599, 27042682 BTK XLR Public db PMID: 18281276, 23765059, 180 25930993, 26029204 CD40LG XLR Public db PMID: 14647476, 17360404, 206 21455173, 23765059, 26008899, 26029204 DNMT3B AR Public db PMID: 23486536, 23765059, 240 26029204, 26851945 DOCK8 AR Public db PMID: 23765059, 23887241, 242 26029204, 26454313 ITK AR Public db PMID: 14647476, 23765059, 308 26029204, 26454313 LCK AR Public db PMID: 14647476, 23765059, 316 26029204, 26454313 PNP AR Both PMID: 26029204, 26454313 354 RAG1 AD AR Public db PMID: 23122631, 23765059, 370 23887241, 25976673, 26029204, 26454313, 27484032, 27808398 STAT1 AD AR Public db PMID: 23887241, 25645939, 436 26029204, 26513235, 26743090, 27821552, 27873163 STAT3 AD Public db PMID: 23765059, 23887241, 438 25645939, 25930993, 26029204, 27658964, 27873163 STK3 un- Both PMID: 26029204 135 known TYK2 AR Public db PMID: 26029204, 26513235, 144 27821552 WAS XLR Both PMID: 12874226, 19782549, 483 20008220, 24753205, 26029204, 26371186 WIPF1 AR Public db PMID: 23765059, 26029204, 485 26453379

TABLE 26 Exemplary 2-gene panel RefSeq NCBI Gene Gene Exon Gene Gene # Symbol overlap ID Description RefSeq Summary (GN) ADA intronic 100 adenosine This gene encodes an enzyme that catalyzes the 1 deaminase hydrolysis of adenosine to inosine. Various mutations have been described for this gene and have been linked to human diseases. Deficiency in this enzyme causes a form of severe combined immunodeficiency disease (SCID), in which there is dysfunction of both B and T lymphocytes with impaired cellular immunity and decreased production of immunoglobulins, whereas elevated levels of this enzyme have been associated with congenital hemolytic anemia. [provided by RefSeq, July 2008]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: BC040226.1, X02994.1 [ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025081, ERS025082 [ECO:0000350] STK3 intronic 6788 serine/threonine- This gene encodes a serine/threonine protein kinase 135 protein kinase 3 activated by proapoptotic molecules indicating the isoform 1 encoded protein functions as a growth suppressor. Cleavage of the protein product by caspase removes the inhibitory C-terminal portion. The N-terminal portion is transported to the nucleus where it homodimerizes to form the active kinase which promotes the condensation of chromatin during apoptosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, January 2012]. Transcript Variant: This variant (1) encodes isoform 1. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: U26424.1, BC010640.2 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025084, ERS025088 [ECO:0000348]

Subjects

A “subject”, as used herein, can be an individual of any age or sex from whom a sample containing polynucleotides is obtained for analysis by one or more methods described herein so as to obtain polynucleic acid information; for example, a male or female adult, child, newborn, or fetus. In some embodiments, a subject can be any target of therapeutic administration. In some embodiments, a subject can be a test subject or a reference subject.

As used herein, a “cohort” can represent an ethnic group, a patient group, a particular age group, a group not associated with a particular condition (e.g., disease or disorder), a group associated with a particular condition (e.g., disease or disorder), a group of asymptomatic subjects, a group of symptomatic subjects, or a group or subgroup of subjects associated with a particular response to a treatment regimen or enrolled in a clinical trial. In some embodiments, a patient can be a subject afflicted with a condition (e.g., disease or disorder). In some embodiments, a patient can be a subject not afflicted with a condition (e.g., disease or disorder) and is considered apparently healthy, or a normal or control subject. In some embodiments, a subject can be a test subject, a patient or a candidate for a therapeutic, wherein genomic DNA from the subject, patient, or candidate is obtained for analysis by one or more methods of the present disclosure herein, so as to obtain genetic variation information of the subject, patient or candidate.

In some embodiments, the polynucleic acid sample can be obtained prenatally from a fetus or embryo or from the mother, for example, from fetal or embryonic cells in the maternal circulation. In some embodiments, the polynucleic acid sample can be obtained with the assistance of a health care provider, for example, to draw blood. In some embodiments, the polynucleic acid sample can be obtained without the assistance of a health care provider, for example, where the polynucleic acid sample is obtained non-invasively, such as a saliva sample, or a sample comprising buccal cells that is obtained using a buccal swab or brush, or a mouthwash sample.

The present disclosure also provides methods for assessing genetic variations in subjects who are members of a target population. Such a target population is in some embodiments a population or group of subjects at risk of developing the condition (e.g., disease or disorder), based on, for example, other genetic factors, biomarkers, biophysical parameters, diagnostic testing such as magnetic resonance imaging (MRI), family history of the condition, previous screening or medical history, or any combination thereof.

The genetic variations of the present disclosure found to be associated with a condition (e.g., disease or disorder) can show similar association in other human populations. Particular embodiments comprising subject human populations are thus also contemplated and within the scope of the disclosure. Such embodiments relate to human subjects that are from one or more human populations including, but not limited to, Caucasian, Ashkenazi Jewish, Sephardi Jewish, European, American, Eurasian, Asian, Central/South Asian, East Asian, Middle Eastern, African, Hispanic, Caribbean, and Oceanic populations. European populations include, but are not limited to, Swedish, Norwegian, Finnish, Russian, Danish, Icelandic, Irish, Celt, English, Scottish, Dutch, Belgian, French, German, Spanish, Portuguese, Italian, Polish, Bulgarian, Slavic, Serbian, Bosnian, Czech, Greek and Turkish populations. The ethnic contribution in subjects can also be determined by genetic analysis, for example, genetic analysis of ancestry can be carried out using unlinked microsatellite markers or single nucleotide polymorphisms (SNPs) such as those set out in Smith et al., (Smith M. W. et al., Am. J. Hum. Genet., 74:1001 (2004)).

Certain genetic variations can have different population frequencies in different populations, or are polymorphic in one population but not in another. The methods available and as thought herein can be applied to practice the present disclosure in any given human population. This can include assessment of genetic variations of the present disclosure, so as to identify those markers that give strongest association within the specific population. Thus, the at-risk variants of the present disclosure can reside on different haplotype background and in different frequencies in various human populations.

Conditions and Immunosuppressive Medications

In some embodiments, a subject can be diagnosed or undiagnosed with a condition (e.g., disease or disorder), can be asymptomatic or symptomatic, can have increased or decreased susceptibility to a condition (e.g., disease or disorder), can be currently under or previously under or not under a treatment for a condition (e.g., disease or disorder), or any combination thereof. In some embodiments, the condition can be AIDS, cancer, organ transplant, or an autoimmune disease. In some embodiments, the condition is PML.

In some embodiments, a subject can be diagnosed or undiagnosed with PML, can be asymptomatic or symptomatic, can have increased or decreased susceptibility to PML, can be currently under or previously under or not under a treatment for PML, or any combination thereof. In some embodiments, a subject can be diagnosed or undiagnosed with AIDS (e.g., individuals infected with HIV), can be asymptomatic or symptomatic, can have increased or decreased susceptibility to AIDS, can be currently under or previously under or not under a treatment for AIDS, or any combination thereof. In some embodiments, a subject can be diagnosed or undiagnosed with cancer (e.g., Hodgkin's disease, leukemia, lymphoma, or myelofibrosis), can be asymptomatic or symptomatic, can have increased or decreased susceptibility to cancer, can be currently under or previously under or not under a treatment for cancer, or any combination thereof. In some embodiments, a subject can be currently diagnosed or previously diagnosed or undiagnosed with an autoimmune disease (e.g., multiple sclerosis, rheumatoid arthritis, psoriasis, systemic lupus erythematosus), can be asymptomatic or symptomatic, can have increased or decreased susceptibility to an autoimmune disease, can be currently under or previously under or not under a treatment for an autoimmune disease, or any combination thereof.

The term “cancer” is meant to include all types of cancerous growths or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness. A metastatic tumor can arise from a multitude of primary tumor types, including but not limited to those of breast, lung, liver, colon and ovarian origin. Examples of cancers include, but are not limited to, a fibrosarcoma, myosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, gastric cancer, esophageal cancer, rectal cancer, pancreatic cancer, ovarian cancer, prostate cancer, uterine cancer, cancer of the head and neck, skin cancer, brain cancer, squamous cell carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, testicular cancer, small cell lung carcinoma, non-small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, myelofibrosis, or Kaposi sarcoma.

The term “autoimmune disease” is meant to include all types of pathological states arising from abnormal immune responses of the body to substances and tissues that are normally present in the body. Examples of autoimmune diseases include, but are not limited to, Addison disease, Anti-NMDA receptor encephalitis, antisynthetase syndrome, Aplastic anemia, autoimmune anemias, Autoimmune hemolytic anemia, Autoimmune pancreatitis, Behcet's Disease, bullous skin disorders, Celiac disease—sprue (gluten-sensitive enteropathy), chronic fatigue syndrome, Chronic inflammatory demyelinating polyneuropathy, chronic lymphocytic leukemia, Crohn's disease, Dermatomyositis, Devic's disease, Erythroblastopenia, Evans syndrome, Focal segmental glomerulosclerosis, Granulomatosis with polyangiitis, Graves disease, Graves' ophthalmopathy, Guillain-Barre syndrome, Hashimoto thyroiditis, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgA-mediated autoimmune diseases, IgG4-related disease, Inflammatory bowel disease, Juvenile idiopathic arthritis, Multiple sclerosis, Myasthenia gravis, myeloma, non-Hodgkin's lymphoma, Opsoclonus myoclonus syndrome (OMS), Pemphigoid, Pemphigus, pemphigus vulgaris, Pernicious anemia, polymyositis, Psoriasis, pure red cell aplasia, Reactive arthritis, Rheumatoid arthritis, Sarcoidosis, scleroderma, Sjögren syndrome, Systemic lupus erythematosus, Thrombocytopenic purpura, Thrombotic thrombocytopenic purpura, Type I diabetes, Ulcerative colitis, Vasculitis (e.g., vasculitis associated with anti-neutrophil cytoplasmic antibody) and Vitiligo.

In some embodiments, a subject can be currently treated with an immunosuppressive medication. In some embodiments, a subject can be previously treated with an immunosuppressive medication. In some embodiments, a subject can be not yet treated with an immunosuppressive medication. The immunosuppressive medication can include but not limited to glucocorticoids, cytostatics, antibodies, drugs acting on immunophilins, interferons, opioids, TNF binding proteins, mycophenolate, or other small biological agents. For example, glucocorticoids can include but not limited to cortisol (hydrocortisone), cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, beclometasone, fludrocortisone acetate, deoxycorticosterone acetate (DOCA), or aldosterone. Cytostatics can include but not limited to nitrogen mustards (e.g., cyclophosphamide), nitrosoureas, platinum compounds, folic acid analogues such as methotrexate, purine analogues such as azathioprine and mercaptopurine, pyrimidine analogues such as fluorouracil, protein synthesis inhibitors, cytotoxic antibiotics such as dactinomycin, anthracyclines, mitomycin C, bleomycin, or mithramycin. Antibodies can include but not limited to polyclonal antibodies such as atgam and thymoglobuline, monoclonal antibodies such as CD25- and CD3-directed antibodies, muromonab-CD3, basiliximab (e.g., SIMULECT), and daclizumab (e.g., ZENAPAX). Drugs acting on immunophilins can include but not limited to ciclosporin, tacrolimus, sirolimus, or everolimus. TNF binding proteins can include but not limited to infliximab (e.g., REMICADE), etanercept (e.g., ENBREL), or adalimumab (e.g., HUMIRA). Other small biological agents can include but not limited to fingolimod, myriocin, and rituximab (e.g., RITUXAN).

In some embodiments, the immunosuppressive medication can be drugs for treating multiple sclerosis include but not limited to interferon beta-1a (e.g., AVONEX, REBIF), interferon beta-1b (e.g., BETASERON, EXTAVIA), glatiramer acetate (e.g., COPAXONE, GLATOPA), peginterferon beta-1a (e.g., PLEGRIDY), teriflunomide (e.g., AUBAGIO), fingolimod (e.g., GILENYA), dimethyl fumarate (e.g., TECFIDERA), alemtuzumab (e.g., LEMTRADA), mitoxantrone (e.g., NOVANTRONE), natalizumab (e.g., TYSABRI), daclizumab (e.g., ZINBRYTA), or ocrelizumab (e.g., OCREVUS).

In some embodiments, the immunosuppressive medication can be adalimumab (e.g., HUMIRA), alemtuzumab (e.g., LEMTRADA), alemtuzumab (e.g., CAMPATH), azathioprine (e.g., IMURAN), belimumab (e.g., BENLYSTA), bevacizumab (e.g., AVASTIN), bortezomib (e.g., VELCADE), eculizumab (e.g., SOLIRIS), leflunomide, brentuximab vedotin (e.g., ADCETRIS), cetuximab (e.g., ERBITUX), cyclophosphamid, dimethyl fumarate (e.g., TECFIDERA), efalizumab (e.g., RAPTIVA), fingolimod (e.g., GILENYA), fludarabine (e.g., FLUDARA), fumaric acid, imatinib (e.g., GLEEVEC, GLIVEC), infliximab (e.g., REMICADE), methotrexate (e.g., TREXALL, RHEUMATREX), mycophenolate mofetil (e.g., CELLCEPT), natalizumab (e.g., TYSABRI), daclizumab (e.g., ZINBRYTA), rituximab (e.g., RITUXAN), vedolizumab (e.g., ENTYVIO), ruxolitinib (e.g., JAKAFI, JAKAVI), or ocrelizumab (e.g., Ocrevus). For example, rituximab can be used to treat MS patients (e.g., off-label), both relapsing-remitting (RRMS) and progressive (PMS) forms; for instance, as reported by Memon A et al. 2018 (PMID 29309416), Alcala C et al. 2018 (PMID 29785523), and Berntsson S et al. 2018 (PMID 29797711).

In some embodiments, a method of treating a condition in a subject in need of natalizumab therapy, comprises administering a therapeutically effective amount of natalizumab to the subject, wherein the subject is identified as not having one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3 and 6. In some embodiments, a method of reducing a risk of a subject developing PML comprises administering a therapeutically effective amount of natalizumab to the subject, wherein the subject is identified as not having one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3 and 6. In some embodiments, the condition is multiple sclerosis. In some embodiments, the condition is Crohn's disease. In some embodiments, a method of treating multiple sclerosis comprises administering natalizumab to a subject with multiple sclerosis, wherein the subject is identified as not having one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3 and 6. In some embodiments, a method of treating Crohn's disease comprises administering natalizumab to a subject with Crohn's disease, wherein the subject is identified as not having one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3 and 6. In some embodiments, a method of treating multiple sclerosis comprises testing a subject with multiple sclerosis for the presence of one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3 and 6, determining that the subject does not have the one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3 and 6, and administering natalizumab to the subject that was determined not to have the one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3 and 6. In some embodiments, a method of treating Crohn's disease comprises testing a subject with Crohn's disease for the presence of one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3 and 6, determining that the subject does not have the one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3 and 6, and administering natalizumab to the subject that was determined not to have the one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3 and 6. In some embodiments, a method of reducing a risk of a subject developing PML comprises testing a subject for the presence of one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3 and 6, determining that the subject has at least one of the one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3 and 6, and advising against administering natalizumab to the subject that was determined to have at least one of the one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3 and 6. In some embodiments, the subject has multiple sclerosis. In some embodiments, the subject has Crohn's disease. In some embodiments, a method of treating multiple sclerosis comprises testing a subject with multiple sclerosis for the presence of one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3 and 6, determining that the subject has at least one of the one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3 and 6, and advising against administering natalizumab to the subject that was determined to have at least one of the one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3 and 6. In some embodiments, a method of treating Crohn's disease comprises testing a subject with Crohn's disease for the presence of one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3 and 6, determining that the subject has at least one of the one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3 and 6, and advising against administering natalizumab to the subject that was determined to have at least one of the one or more genetic variations that disrupt or modulate a corresponding gene according to Tables 3 and 6. In some embodiments, the advising comprises advising that administering natalizumab is contraindicated. In some embodiments, the advising comprises advising that administering natalizumab increases the risk of the subject developing PML. In some embodiments, the advising comprises advising that administering natalizumab is a factor that increases the risk of the subject developing PML.

Samples

Samples that are suitable for use in the methods described herein can be polynucleic acid samples from a subject. A “polynucleic acid sample” as used herein can include RNA or DNA, or a combination thereof. In another embodiment, a “polypeptide sample” (e.g., peptides or proteins, or fragments therefrom) can be used to ascertain information that an amino acid change has occurred, which is the result of a genetic variant. Polynucleic acids and polypeptides can be extracted from one or more samples including but not limited to, blood, saliva, urine, mucosal scrapings of the lining of the mouth, expectorant, serum, tears, skin, tissue, or hair. A polynucleic acid sample can be assayed for polynucleic acid information. “Polynucleic acid information,” as used herein, includes a polynucleic acid sequence itself, the presence/absence of genetic variation in the polynucleic acid sequence, a physical property which varies depending on the polynucleic acid sequence (e.g., Tm), and the amount of the polynucleic acid (e.g., number of mRNA copies). A “polynucleic acid” means any one of DNA, RNA, DNA including artificial nucleotides, or RNA including artificial nucleotides. As used herein, a “purified polynucleic acid” includes cDNAs, fragments of genomic polynucleic acids, polynucleic acids produced using the polymerase chain reaction (PCR), polynucleic acids formed by restriction enzyme treatment of genomic polynucleic acids, recombinant polynucleic acids, and chemically synthesized polynucleic acid molecules. A “recombinant” polynucleic acid molecule includes a polynucleic acid molecule made by an artificial combination of two otherwise separated segments of sequence, e.g., by chemical synthesis or by the manipulation of isolated segments of polynucleic acids by genetic engineering techniques. As used herein, a “polypeptide” includes proteins, fragments of proteins, and peptides, whether isolated from natural sources, produced by recombinant techniques, or chemically synthesized. A polypeptide may have one or more modifications, such as a post-translational modification (e.g., glycosylation, phosphorylation, etc.) or any other modification (e.g., pegylation, etc.). The polypeptide may contain one or more non-naturally-occurring amino acids (e.g., such as an amino acid with a side chain modification).

In some embodiments, the polynucleic acid sample can comprise cells or tissue, for example, cell lines. Exemplary cell types from which nucleic acids can be obtained using the methods described herein include, but are not limited to, the following: a blood cell such as a B lymphocyte, T lymphocyte, leukocyte, erythrocyte, macrophage, or neutrophil; a muscle cell such as a skeletal cell, smooth muscle cell or cardiac muscle cell; a germ cell, such as a sperm or egg; an epithelial cell; a connective tissue cell, such as an adipocyte, chondrocyte; fibroblast or osteoblast; a neuron; an astrocyte; a stromal cell; an organ specific cell, such as a kidney cell, pancreatic cell, liver cell, or a keratinocyte; a stem cell; or any cell that develops therefrom. A cell from which nucleic acids can be obtained can be a blood cell or a particular type of blood cell including, for example, a hematopoietic stem cell or a cell that arises from a hematopoietic stem cell such as a red blood cell, B lymphocyte, T lymphocyte, natural killer cell, neutrophil, basophil, eosinophil, monocyte, macrophage, or platelet. Generally, any type of stem cell can be used including, without limitation, an embryonic stem cell, adult stem cell, or pluripotent stem cell.

In some embodiments, a polynucleic acid sample can be processed for RNA or DNA isolation, for example, RNA or DNA in a cell or tissue sample can be separated from other components of the polynucleic acid sample. Cells can be harvested from a polynucleic acid sample using standard techniques, for example, by centrifuging a cell sample and resuspending the pelleted cells, for example, in a buffered solution, for example, phosphate-buffered saline (PBS). In some embodiments, after centrifuging the cell suspension to obtain a cell pellet, the cells can be lysed to extract DNA. In some embodiments, the nucleic acid sample can be concentrated and/or purified to isolate DNA. All nucleic acid samples obtained from a subject, including those subjected to any sort of further processing, are considered to be obtained from the subject. In some embodiments, standard techniques and kits known in the art can be used to extract RNA or DNA from a nucleic acid sample, including, for example, phenol extraction, a QIAAMP® Tissue Kit (Qiagen, Chatsworth, Calif.), a WIZARD® Genomic DNA purification kit (Promega), or a Qiagen Autopure method using Puregene chemistry, which can enable purification of highly stable DNA well-suited for archiving.

In some embodiments, determining the identity of an allele or determining copy number can, but need not, include obtaining a polynucleic acid sample comprising RNA and/or DNA from a subject, and/or assessing the identity, copy number, presence or absence of one or more genetic variations and their chromosomal locations within the genomic DNA (e.g. subject's genome) derived from the polynucleic acid sample.

The individual or organization that performs the determination need not actually carry out the physical analysis of a nucleic acid sample from a subject. In some embodiments, the methods can include using information obtained by analysis of the polynucleic acid sample by a third party. In some embodiments, the methods can include steps that occur at more than one site. For example, a polynucleic acid sample can be obtained from a subject at a first site, such as at a health care provider or at the subject's home in the case of a self-testing kit. The polynucleic acid sample can be analyzed at the same or a second site, for example, at a laboratory or other testing facility.

Nucleic Acids

The nucleic acids and polypeptides described herein can be used in methods and kits of the present disclosure. In some embodiments, aptamers that specifically bind the nucleic acids and polypeptides described herein can be used in methods and kits of the present disclosure. As used herein, a nucleic acid can comprise a deoxyribonucleotide (DNA) or ribonucleotide (RNA), whether singular or in polymers, naturally occurring or non-naturally occurring, double-stranded or single-stranded, coding, for example a translated gene, or non-coding, for example a regulatory region, or any fragments, derivatives, mimetics or complements thereof. In some embodiments, nucleic acids can comprise oligonucleotides, nucleotides, polynucleotides, nucleic acid sequences, genomic sequences, complementary DNA (cDNA), antisense nucleic acids, DNA regions, probes, primers, genes, regulatory regions, introns, exons, open-reading frames, binding sites, target nucleic acids and allele-specific nucleic acids.

A “probe,” as used herein, includes a nucleic acid fragment for examining a nucleic acid in a specimen using the hybridization reaction based on the complementarity of nucleic acid.

A “hybrid” as used herein, includes a double strand formed between any one of the abovementioned nucleic acid, within the same type, or across different types, including DNA-DNA, DNA-RNA, RNA-RNA or the like.

“Isolated” nucleic acids, as used herein, are separated from nucleic acids that normally flank the gene or nucleotide sequence (as in genomic sequences) and/or has been completely or partially purified from other transcribed sequences (e.g., as in an RNA library). For example, isolated nucleic acids of the disclosure can be substantially isolated with respect to the complex cellular milieu in which it naturally occurs, or culture medium when produced by recombinant techniques, or chemical precursors or other chemicals when chemically synthesized. In some instances, the isolated material can form part of a composition, for example, a crude extract containing other substances, buffer system or reagent mix. In some embodiments, the material can be purified to essential homogeneity using methods known in the art, for example, by polyacrylamide gel electrophoresis (PAGE) or column chromatography (e.g., HPLC). With regard to genomic DNA (gDNA), the term “isolated” also can refer to nucleic acids that are separated from the chromosome with which the genomic DNA is naturally associated. For example, the isolated nucleic acid molecule can contain less than about 250 kb, 200 kb, 150 kb, 100 kb, 75 kb, 50 kb, 25 kb, 10 kb, 5 kb, 4 kb, 3 kb, 2 kb, 1 kb, 0.5 kb or 0.1 kb of the nucleotides that flank the nucleic acid molecule in the gDNA of the cell from which the nucleic acid molecule is derived.

Nucleic acids can be fused to other coding or regulatory sequences can be considered isolated. For example, recombinant DNA contained in a vector is included in the definition of “isolated” as used herein. In some embodiments, isolated nucleic acids can include recombinant DNA molecules in heterologous host cells or heterologous organisms, as well as partially or substantially purified DNA molecules in solution. Isolated nucleic acids also encompass in vivo and in vitro RNA transcripts of the DNA molecules of the present disclosure. An isolated nucleic acid molecule or nucleotide sequence can be synthesized chemically or by recombinant means. Such isolated nucleotide sequences can be useful, for example, in the manufacture of the encoded polypeptide, as probes for isolating homologous sequences (e.g., from other mammalian species), for gene mapping (e.g., by in situ hybridization with chromosomes), or for detecting expression of the gene, in tissue (e.g., human tissue), such as by Northern blot analysis or other hybridization techniques disclosed herein. The disclosure also pertains to nucleic acid sequences that hybridize under high stringency hybridization conditions, such as for selective hybridization, to a nucleotide sequence described herein Such nucleic acid sequences can be detected and/or isolated by allele- or sequence-specific hybridization (e.g., under high stringency conditions). Stringency conditions and methods for nucleic acid hybridizations are well known to the skilled person (see, e.g., Current Protocols in Molecular Biology, Ausubel, F. et al., John Wiley & Sons, (1998), and Kraus, M. and Aaronson, S., Methods Enzymol., 200:546-556 (1991), the entire teachings of which are incorporated by reference herein.

Calculations of “identity” or “percent identity” between two or more nucleotide or amino acid sequences can be determined by aligning the sequences for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first sequence). The nucleotides at corresponding positions are then compared, and the percent identity between the two sequences is a function of the number of identical positions shared by the sequences (e.g. % identity=# of identical positions/total # of positions×100). For example, a position in the first sequence is occupied by the same nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.

In some embodiments, the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%, of the length of the reference sequence. The actual comparison of the two sequences can be accomplished by well-known methods, for example, using a mathematical algorithm. A non-limiting example of such a mathematical algorithm is described in Karlin, S. and Altschul, S., Proc. Natl. Acad. Sci. USA, 90-5873-5877 (1993). Such an algorithm is incorporated into the NBLAST and XBLAST programs (version 2.0), as described in Altschul, S. et al., Nucleic Acids Res., 25:3389-3402 (1997). When utilizing BLAST and Gapped BLAST programs, any relevant parameters of the respective programs (e.g., NBLAST) can be used. For example, parameters for sequence comparison can be set at score=100, word length=12, or can be varied (e.g., W=5 or W=20). Other examples include the algorithm of Myers and Miller, CABIOS (1989), ADVANCE, ADAM, BLAT, and FASTA. In some embodiments, the percent identity between two amino acid sequences can be accomplished using, for example, the GAP program in the GCG software package (Accelrys, Cambridge, UK).

“Probes” or “primers” can be oligonucleotides that hybridize in a base-specific manner to a complementary strand of a nucleic acid molecule. Probes can include primers, which can be a single-stranded oligonucleotide probe that can act as a point of initiation of template-directed DNA synthesis using methods including but not limited to, polymerase chain reaction (PCR) and ligase chain reaction (LCR) for amplification of a target sequence. Oligonucleotides, as described herein, can include segments or fragments of nucleic acid sequences, or their complements. In some embodiments, DNA segments can be between 5 and 10,000 contiguous bases, and can range from 5, 10, 12, 15, 20, or 25 nucleotides to 10, 15, 20, 25, 30, 40, 50, 100, 200, 500, 1000 or 10,000 nucleotides. In addition to DNA and RNA, probes and primers can include polypeptide nucleic acids (PNA), as described in Nielsen, P. et al., Science 254: 1497-1500 (1991). A probe or primer can comprise a region of nucleotide sequence that hybridizes to at least about 15, typically about 20-25, and in certain embodiments about 40, 50, 60 or 75, consecutive nucleotides of a nucleic acid molecule.

The present disclosure also provides isolated nucleic acids, for example, probes or primers, that contain a fragment or portion that can selectively hybridize to a nucleic acid that comprises, or consists of, a nucleotide sequence, wherein the nucleotide sequence can comprise at least one polymorphism or polymorphic allele contained in the genetic variations described herein or the wild-type nucleotide that is located at the same position, or the complements thereof. In some embodiments, the probe or primer can be at least 70% identical, at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical, to the contiguous nucleotide sequence or to the complement of the contiguous nucleotide sequence.

In some embodiments, a nucleic acid probe can be an oligonucleotide capable of hybridizing with a complementary region of a gene associated with a condition (e.g., PML) containing a genetic variation described herein. The nucleic acid fragments of the disclosure can be used as probes or primers in assays such as those described herein.

The nucleic acids of the disclosure, such as those described above, can be identified and isolated using standard molecular biology techniques well known to the skilled person. In some embodiments, DNA can be amplified and/or can be labeled (e.g., radiolabeled, fluorescently labeled) and used as a probe for screening, for example, a cDNA library derived from an organism. cDNA can be derived from mRNA and can be contained in a suitable vector. For example, corresponding clones can be isolated, DNA obtained following in vivo excision, and the cloned insert can be sequenced in either or both orientations by art-recognized methods to identify the correct reading frame encoding a polypeptide of the appropriate molecular weight. Using these or similar methods, the polypeptide and the DNA encoding the polypeptide can be isolated, sequenced and further characterized.

In some embodiments, nucleic acid can comprise one or more polymorphisms, variations, or mutations, for example, single nucleotide polymorphisms (SNPs), single nucleotide variations (SNVs), copy number variations (CNVs), for example, insertions, deletions, inversions, and translocations. In some embodiments, nucleic acids can comprise analogs, for example, phosphorothioates, phosphoramidates, methyl phosphonate, chiralmethyl phosphonates, 2-O-methyl ribonucleotides, or modified nucleic acids, for example, modified backbone residues or linkages, or nucleic acids combined with carbohydrates, lipids, polypeptide or other materials, or peptide nucleic acids (PNAs), for example, chromatin, ribosomes, and transcriptosomes. In some embodiments nucleic acids can comprise nucleic acids in various structures, for example, A DNA, B DNA, Z-form DNA, siRNA, tRNA, and ribozymes. In some embodiments, the nucleic acid may be naturally or non-naturally polymorphic, for example, having one or more sequence differences, for example, additions, deletions and/or substitutions, as compared to a reference sequence. In some embodiments, a reference sequence can be based on publicly available information, for example, the U.C. Santa Cruz Human Genome Browser Gateway (genome.ucsc.edu/cgi-bin/hgGateway) or the NCBI website (www.ncbi.nlm.nih.gov). In some embodiments, a reference sequence can be determined by a practitioner of the present disclosure using methods well known in the art, for example, by sequencing a reference nucleic acid.

In some embodiments, a probe can hybridize to an allele, SNP, SNV, or CNV as described herein. In some embodiments, the probe can bind to another marker sequence associated with PML as described herein.

One of skill in the art would know how to design a probe so that sequence specific hybridization can occur only if a particular allele is present in a genomic sequence from a test nucleic acid sample. The disclosure can also be reduced to practice using any convenient genotyping method, including commercially available technologies and methods for genotyping particular genetic variations

Control probes can also be used, for example, a probe that binds a less variable sequence, for example, a repetitive DNA associated with a centromere of a chromosome, can be used as a control. In some embodiments, probes can be obtained from commercial sources. In some embodiments, probes can be synthesized, for example, chemically or in vitro, or made from chromosomal or genomic DNA through standard techniques. In some embodiments sources of DNA that can be used include genomic DNA, cloned DNA sequences, somatic cell hybrids that contain one, or a part of one, human chromosome along with the normal chromosome complement of the host, and chromosomes purified by flow cytometry or microdissection. The region of interest can be isolated through cloning, or by site-specific amplification using PCR.

One or more nucleic acids for example, a probe or primer, can also be labeled, for example, by direct labeling, to comprise a detectable label. A detectable label can comprise any label capable of detection by a physical, chemical, or a biological process for example, a radioactive label, such as ³²P or ³H, a fluorescent label, such as FITC, a chromophore label, an affinity-ligand label, an enzyme label, such as alkaline phosphatase, horseradish peroxidase, or 12 galactosidase, an enzyme cofactor label, a hapten conjugate label, such as digoxigenin or dinitrophenyl, a Raman signal generating label, a magnetic label, a spin label, an epitope label, such as the FLAG or HA epitope, a luminescent label, a heavy atom label, a nanoparticle label, an electrochemical label, a light scattering label, a spherical shell label, semiconductor nanocrystal label, such as quantum dots (described in U.S. Pat. No. 6,207,392), and probes labeled with any other signal generating label known to those of skill in the art, wherein a label can allow the probe to be visualized with or without a secondary detection molecule. A nucleotide can be directly incorporated into a probe with standard techniques, for example, nick translation, random priming, and PCR labeling. A “signal,” as used herein, include a signal suitably detectable and measurable by appropriate means, including fluorescence, radioactivity, chemiluminescence, and the like.

Non-limiting examples of label moieties useful for detection include, without limitation, suitable enzymes such as horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase; members of a binding pair that are capable of forming complexes such as streptavidin/biotin, avidin/biotin or an antigen/antibody complex including, for example, rabbit IgG and anti-rabbit IgG; fluorophores such as umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, tetramethyl rhodamine, eosin, green fluorescent protein, erythrosin, coumarin, methyl coumarin, pyrene, malachite green, stilbene, lucifer yellow, Cascade Blue, Texas Red, dichlorotriazinylamine fluorescein, dansyl chloride, phycoerythrin, fluorescent lanthanide complexes such as those including Europium and Terbium, cyanine dye family members, such as Cy3 and Cy5, molecular beacons and fluorescent derivatives thereof, as well as others known in the art as described, for example, in Principles of Fluorescence Spectroscopy, Joseph R. Lakowicz (Editor), Plenum Pub Corp, 2nd edition (July 1999) and the 6th Edition of the Molecular Probes Handbook by Richard P. Hoagland; a luminescent material such as luminol; light scattering or plasmon resonant materials such as gold or silver particles or quantum dots; or radioactive material include ¹⁴C, ¹²³I, ¹²⁴I, ¹²⁵I, Tc99m, ³²P, ³³P, ³⁵S or ³H.

Other labels can also be used in the methods of the present disclosure, for example, backbone labels. Backbone labels comprise nucleic acid stains that bind nucleic acids in a sequence independent manner. Non-limiting examples include intercalating dyes such as phenanthridines and acridines (e.g., ethidium bromide, propidium iodide, hexidium iodide, dihydroethidium, ethidium homodimer-1 and -2, ethidium monoazide, and ACMA); some minor grove binders such as indoles and imidazoles (e.g., Hoechst 33258, Hoechst 33342, Hoechst 34580 and DAPI); and miscellaneous nucleic acid stains such as acridine orange (also capable of intercalating), 7-AAD, actinomycin D, LDS751, and hydroxystilbamidine. All of the aforementioned nucleic acid stains are commercially available from suppliers such as Molecular Probes, Inc. Still other examples of nucleic acid stains include the following dyes from Molecular Probes: cyanine dyes such as SYTOX Blue, SYTOX Green, SYTOX Orange, POPO-1, POPO-3, YOYO-1, YOYO-3, TOTO-1, TOTO-3, JOJO-1, LOLO-1, BOBO-1, BOBO-3, PO-PRO-1, PO-PRO-3, BO-PRO-1, BO-PRO-3, TO-PRO-1, TO-PRO-3, TO-PRO-5, JO-PRO-1, LO-PRO-1, YO-PRO-1, YO-PRO-3, PicoGreen, OliGreen, RiboGreen, SYBR Gold, SYBR Green I, SYBR Green II, SYBR DX, SYTO-40, -41, -42, -43, -44, -45 (blue), SYTO-13, -16, -24, -21, -23, -12, -11, -20, -22, -15, -14, -25 (green), SYTO-81, -80, -82, -83, -84, -85 (orange), SYTO-64, -17, -59, -61, -62, -60, -63 (red).

In some embodiments, fluorophores of different colors can be chosen, for example, 7-amino-4-methylcoumarin-3-acetic acid (AMCA), 5-(and-6)-carboxy-X-rhodamine, lissamine rhodamine B, 5-(and-6)-carboxyfluorescein, fluorescein-5-isothiocyanate (FITC), 7-diethylaminocoumarin-3-carboxylic acid, tetramethylrhodamine-5-(and-6)-isothiocyanate, 5-(and-6)-carboxytetramethylrhodamine, 7-hydroxycoumarin-3-carboxylic acid, 6-[fluorescein 5-(and-6)-carboxamido]hexanoic acid, N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a diaza-3-indacenepropionic acid, eosin-5-isothiocyanate, erythrosin-5-isothiocyanate, TRITC, rhodamine, tetramethylrhodamine, R-phycoerythrin, Cy-3, Cy-5, Cy-7, Texas Red, Phar-Red, allophycocyanin (APC), and CASCADE™ blue acetylazide, such that each probe in or not in a set can be distinctly visualized. In some embodiments, fluorescently labeled probes can be viewed with a fluorescence microscope and an appropriate filter for each fluorophore, or by using dual or triple band-pass filter sets to observe multiple fluorophores. In some embodiments, techniques such as flow cytometry can be used to examine the hybridization pattern of the probes.

In other embodiments, the probes can be indirectly labeled, for example, with biotin or digoxygenin, or labeled with radioactive isotopes such as ³²P and/or ³H. As a non-limiting example, a probe indirectly labeled with biotin can be detected by avidin conjugated to a detectable marker. For example, avidin can be conjugated to an enzymatic marker such as alkaline phosphatase or horseradish peroxidase. In some embodiments, enzymatic markers can be detected using colorimetric reactions using a substrate and/or a catalyst for the enzyme. In some embodiments, catalysts for alkaline phosphatase can be used, for example, 5-bromo-4-chloro-3-indolylphosphate and nitro blue tetrazolium. In some embodiments, a catalyst can be used for horseradish peroxidase, for example, diaminobenzoate.

One or more genes disclosed herein can be in conditions or molecular pathways related to various aspects of immune function including, but not limited to, Type I interferon response (e.g., PMID 26052098), B cell receptor pathway (e.g., Wikipathways WP23; PMID 22566564), RANKL/RANK signaling pathway (e.g., Wikipathways WP2018), TCR signaling pathway (e.g., Wikipathways WP69), NF-kB signaling (e.g., PMID 28362430), JAK-STAT pathway (e.g., PMID 28255960), post-translational modification biology such as ubiquitination via LUBAC (e.g., PMID 23104095, 24958845, 25086647, 26085218, 26111062, 26525107, 26848516, 26877205, 27178468, 27786304, 27892465), Aicardi-Goutieres syndrome (e.g., PMID 26052098), eosinophilia (e.g., PMID 27222657), congenital neutropenia (e.g., PMID 24753205), T cell receptor defects (e.g., PMID 25452106, 25636200, 26246585, 26379669, 26453379, 28400082), and autophagy defects (e.g., 19229298, 22984599, 23222957, 26917586, 26953272, 27588602). In some embodiments, one or more genes disclosed herein can be related to JC virus biology (e.g., PMID 15327898, 19282432, 19903823, 22984599, 25910481). In some embodiments, one or more genes disclosed herein can be antibiral immune response genes.

TABLE 27 Exemplary pathways and biology for PML risk genes (96-gene panel) B cell Eosino- T cell Type I Auto- B re- philia- JC PI3K RANKL/ T re- TLR inter- inflam- Auto- cell ceptor Deubi- associated virus sig- RANK cell ceptor sig- feron matory phagy de- path- quitinase immuno- bio- Osteo- nal - path- de- path- nal - path- Genes disease defects fects way pathway deficiency logy petrosis ing way fects way ing way AP3B1 x APOL1 x ASH1L ATM x x x x ATR x x BLM CARD11 x x x x x CDKN1B CHD7 x CLCN7 x DCLRE1C DDX5 8 x DOCK8 x x x EGR1 EPG5 x ETF1 FPR2 GATA2 x GFI1 x HIVEP1 HIVEP2 HTR2A x IDO2 IFIH1 x IFNGR2 IFNLR1 IGLL1 x x IKBKB x x x x x x x x x IL17F IL1B x x x x x IL21R x IRAK4 x x x x x ITSN2 JUN x x x KAT6B KCTD7 LIG4 x LRBA x x x MALL MAPK3 x x x x MAVS x MCEE MKL1 x MYD88 x x x x NBN NFKB1 x x x x x x x x x x NOD2 x x x x x NRIP1 PIAS1 x PIAS2 x PIK3CD x x PIK3CD-AS1 x PIK3R1 x x x x x x PKHD1 PLCG2 x x x x x x x PNPT1 POLA1 x POLE x PRF1 PRKCB x PRKCD x x x PRKCH PRKDC x PSTPIP1 x PTEN x PTPRC x x x RABGEF1 RAD51 x RAG1 x x x RAG2 x x x RIPK1 x x x x RIPK3 x x RNF168 RTEL1 SHARPIN x x x x x x SKIV2L x SMAD4 x STIM1 x x STIM2 STXBP2 TAP2 TBK1 x x TCIRG1 x TICAM1 x x x TLR3 x x x x TLR4 x x x x TNFRSF11A x x x x x x TNFRSF13B x x TNFRSF8 TP53 TRAF3 x x x x TRAFD1 x x x TRPM2 VPS45 WEE1 x ZAP70 x x x x

Table 27 contains a set of exemplary pathways and biology for PML risk genes based on the 96-gene panel listed in Table 19. The genes disclosed herein, such as the genes in the 96-gene panel, can be grouped based on the pathway or biological processes they are involved in.

Methods of Screening

As used herein, screening a subject comprises diagnosing or determining, theranosing, or determining the susceptibility to developing (prognosing) a condition, for example, PML. In particular embodiments, the disclosure is a method of determining a presence of, or a susceptibility to, PML, by detecting at least one genetic variation in a sample from a subject as described herein. In some embodiments, detection of particular alleles, markers, variations, or haplotypes is indicative of a presence or susceptibility to a condition (e.g., PML).

While means for screening PML using a JCV antibody test exist, PML risk is not adequately assessed by the JCV antibody test alone. Thus there exists a need for an improved screening test for assessing the risk of developing PML. Described herein are methods of screening an individual for a risk of developing PML, including but not limited to, determining the identity and location of genetic variations, such as variations in nucleotide sequence and copy number, and the presence or absence of alleles or genotypes in one or more samples from one or more subjects using any of the methods described herein. In some embodiments, determining an association to having or developing PML can be performed by detecting particular variations that appear more frequently in test subjects compared to reference subjects and analyzing the molecular and physiological pathways these variations can affect.

Within any given population, there can be an absolute susceptibility of developing a disease or trait, defined as the chance of a person developing the specific disease or trait over a specified time-period. Susceptibility (e.g., being at-risk) is typically measured by looking at very large numbers of people, rather than at a particular individual. As described herein, certain copy number variations (genetic variations) and/or single nucleotide variations are found to be useful for susceptibility assessment of PML. Susceptibility assessment can involve detecting particular genetic variations in the genome of individuals undergoing assessment. Particular genetic variations are found more frequently in individuals with PML, than in individuals without PML. Therefore, these genetic variations have predictive value for detecting PML, or a susceptibility to PML, in an individual. Without intending to be limited by theory, it is believed that the genetic variations described herein to be associated with susceptibility of PML represent functional variants predisposing to the disease. In some embodiments, a genetic variation can confer a susceptibility of the condition, for example carriers of the genetic variation are at a different risk of the condition than non-carriers. In some embodiments, the presence of a genetic variation is indicative of increased susceptibility to PML.

In some embodiments, screening can be performed using any of the methods disclosed, alone or in combination. In some embodiments, screening can be performed using Polymerase Chain Reaction (PCR). In some embodiments screening can be performed using Array Comparative Genomic Hybridization (aCGH) to detect CNVs. In another preferred embodiment screening can be performed using exome sequencing to detect SNVs, indels, and in some cases CNVs using appropriate analysis algorithms. In another preferred embodiment screening is performed using high-throughput (also known as next generation) whole genome sequencing methods and appropriate algorithms to detect all or nearly all genetic variations present in a genomic DNA sample. In some embodiments, the genetic variation information as it relates to the current disclosure can be used in conjunction with any of the above mentioned symptomatic screening tests to screen a subject for PML, for example, using a combination of aCGH and/or sequencing with a JCV screening test, such as the JCV antibody test, CD62L test, or CSF IgM oligoclonal band test. In some embodiments, the L-selectin (CD62L) expressed by CD3⁺CD4⁺ T cells in, for example, cryopreserved peripheral blood mononuclear cells (PBMCs), can be a biomarker for JCV screening. A CD62L expression can be correlated with the risk of PML.

In some embodiments, information from any of the above screening methods (e.g., specific symptoms, scoring matrix, or genetic variation data) can be used to define a subject as a test subject or reference subject. In some embodiments, information from any of the above screening methods can be used to associate a subject with a test or reference population, for example, a subject in a population.

In one embodiment, an association with PML can be determined by the statistical likelihood of the presence of a genetic variation in a subject with PML, for example, an unrelated individual or a first or second-degree relation of the subject. In some embodiments, an association with PML can be decided by determining the statistical likelihood of the absence of a genetic variation in an unaffected reference subject, for example, an unrelated individual or a first or second-degree relation of the subject. The methods described herein can include obtaining and analyzing a nucleic acid sample from one or more suitable reference subjects.

In the present context, the term screening comprises diagnosis, prognosis, and theranosis. Screening can refer to any available screening method, including those mentioned herein. As used herein, susceptibility can be proneness of a subject towards the development of PML, or towards being less able to resist PML than one or more control subjects. In some embodiments, susceptibility can encompass increased susceptibility. For example, particular nucleic acid variations of the disclosure as described herein can be characteristic of increased susceptibility to PML. In some embodiments, particular nucleic acid variations can confer decreased susceptibility, for example particular nucleic variations of the disclosure as described herein can be characteristic of decreased susceptibility to development of PML.

As described herein, a genetic variation predictive of susceptibility to or presence of PML can be one where the particular genetic variation is more frequently present in a group of subjects with the condition (affected), compared to the frequency of its presence in a reference group (control), such that the presence of the genetic variation is indicative of susceptibility to or presence of PML. In some embodiments, the reference group can be a population nucleic acid sample, for example, a random nucleic acid sample from the general population or a mixture of two or more nucleic acid samples from a population. In some embodiments, disease-free controls can be characterized by the absence of one or more specific disease-associated symptoms, for example, individuals who have not experienced symptoms associated with PML. In some embodiments, the disease-free control group is characterized by the absence of one or more disease-specific risk factors, for example, at least one genetic and/or environmental risk factor. In some embodiments, a reference sequence can be referred to for a particular site of genetic variation. In some embodiments, a reference allele can be a wild-type allele and can be chosen as either the first sequenced allele or as the allele from a control individual. In some embodiments, one or more reference subjects can be characteristically matched with one or more affected subjects, for example, with matched aged, gender or ethnicity.

A person skilled in the art can appreciate that for genetic variations with two or more alleles present in the population being studied, and wherein one allele can be found in increased frequency in a group of individuals with PML in the population, compared with controls, the other allele of the marker can be found in decreased frequency in the group of individuals with the trait or disease, compared with controls. In such a case, one allele of the marker, for example, the allele found in increased frequency in individuals with PML, can be the at-risk allele, while the other allele(s) can be a neutral or protective allele.

A genetic variant associated with PML can be used to predict the susceptibility of the disease for a given genotype. For any genetic variation, there can be one or more possible genotypes, for example, homozygote for the at-risk variant (e.g., in autosomal recessive disorders), heterozygote, and non-carrier of the at-risk variant. Autosomal recessive disorders can also result from two distinct genetic variants impacting the same gene such that the individual is a compound heterozygote (e.g., the maternal allele contains a different mutation than the paternal allele). Compound heterozygosity may result from two different SNVs, two different CNVs, an SNV and a CNV, or any combination of two different genetic variants but each present on a different allele for the gene. For X-linked genes, males who possess one copy of a variant-containing gene may be affected, while carrier females, who also possess a wild-type gene, may remain unaffected. In some embodiments, susceptibility associated with variants at multiple loci can be used to estimate overall susceptibility. For multiple genetic variants, there can be k (k=3{circumflex over ( )}n*2{circumflex over ( )}P) possible genotypes; wherein n can be the number of autosomal loci and p can be the number of gonosomal (sex chromosomal) loci. Overall susceptibility assessment calculations can assume that the relative susceptibilities of different genetic variants multiply, for example, the overall susceptibility associated with a particular genotype combination can be the product of the susceptibility values for the genotype at each locus. If the susceptibility presented is the relative susceptibility for a person, or a specific genotype for a person, compared to a reference population, then the combined susceptibility can be the product of the locus specific susceptibility values and can correspond to an overall susceptibility estimate compared with a population. If the susceptibility for a person is based on a comparison to non-carriers of the at-risk allele, then the combined susceptibility can correspond to an estimate that compares the person with a given combination of genotypes at all loci to a group of individuals who do not carry at-risk variants at any of those loci. The group of non-carriers of any at-risk variant can have the lowest estimated susceptibility and can have a combined susceptibility, compared with itself, for example, non-carriers, of 1.0, but can have an overall susceptibility, compared with the population, of less than 1.0.

Overall risk for multiple risk variants can be performed using standard methodology. Genetic variations described herein can form the basis of risk analysis that combines other genetic variations known to increase risk of PML, or other genetic risk variants for PML. In certain embodiments of the disclosure, a plurality of variants (genetic variations, variant alleles, and/or haplotypes) can be used for overall risk assessment. These variants are in some embodiments selected from the genetic variations as disclosed herein. Other embodiments include the use of the variants of the present disclosure in combination with other variants known to be useful for screening a susceptibility to PML. In such embodiments, the genotype status of a plurality of genetic variations, markers and/or haplotypes is determined in an individual, and the status of the individual compared with the population frequency of the associated variants, or the frequency of the variants in clinically healthy subjects, such as age-matched and sex-matched subjects.

Methods such as the use of available algorithms and software can be used to identify, or call, significant genetic variations, including but not limited to, algorithms of DNA Analytics or DNAcopy, iPattem and/or QuantiSNP. In some embodiments, a threshold logratio value can be used to determine losses and gains. For example, using DNA Analytics, a log₂ ratio cutoff of ≥0.5 and ≤0.5 to classify CNV gains and losses respectively can be used. For example, using DNA Analytics, a log₂ ratio cutoff of ≥0.25 and ≤0.25 to classify CNV gains and losses respectively can be used. As a further example, using DNAcopy, a log₂ ratio cutoff of ≥0.35 and ≤0.35 to classify CNV gains and losses respectively can be used. For example, an Aberration Detection Module 2 (ADM2) algorithm, such as that of DNA Analytics 4.0.85 can be used to identify, or call, significant genetic variations. In some embodiments, two or more algorithms can be used to identify, or call, significant genetic variations. For example, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more algorithms can be used to identify, or call, significant genetic variations. In another embodiment, the log 2 ratio of one or more individual probes on a microarray can be used to identify significant genetic variations, such as the presence of homozygously deleted regions in a subject's genome. In some embodiments, significant genetic variations can be CNVs.

CNVs detected by two or more algorithms can be defined as stringent and can be utilized for further analyses. In some embodiments, the information and calls from two or more of the methods described herein can be compared to each other to identify significant genetic variations more or less stringently. For example, CNV calls generated by two or more of DNA Analytics, Aberration Detection Module 2 (ADM2) algorithms, and DNAcopy algorithms can be defined as stringent CNVs. In some embodiments significant or stringent genetic variations can be tagged as identified or called if it can be found to have a minimal reciprocal overlap to a genetic variation detected by one or more platforms and/or methods described herein. For example, a minimum of 50% reciprocal overlap can be used to tag the CNVs as identified or called. For example, significant or stringent genetic variations can be tagged as identified or called if it can be found to have a reciprocal overlap of more than about 50%, 55% 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, 99%, or equal to 100%, to a genetic variation detected by one or more platforms and/or methods described herein. For example, significant or stringent genetic variations can be tagged as identified or called if it can be found to have a reciprocal overlap of more than about 50% reciprocal overlap to a genetic variation detected by one or more platforms and/or methods described herein. In another embodiment, genetic variations can be detected from the log 2 ratio values calculated for individual probes present on an aCGH microarray via a statistical comparison of the probe's log 2 ratio value in a cohort of subjects with PML to the probe's log 2 ratio value in a cohort of subjects without PML.

In some embodiments, a threshold log ratio value can be used to determine losses and gains. A log ratio value can be any log ratio value; for example, a log ratio value can be a log 2 ratio or a log 10 ratio. In some embodiments, a CNV segment whose median log 2 ratio is less than or equal to a log 2 ratio threshold value can be classified as a loss. For example, any segment whose median log 2 ratio is less than or equal to −0.1, −0.11, −0.12, −0.13, −0.14, −0.15, −0.16, −0.17, −0.18, −0.19, −0.2, −0.21, −0.22, −0.23, −0.24, −0.25, −0.26, −0.27, −0.28, −0.29, −0.3, −0.31, −0.32, −0.33, −0.34, −0.35, −0.36, −0.37, −0.38, −0.39, −0.4, −0.41, −0.42, −0.43, −0.44, −0.45, −0.46, −0.47, −0.48, −0.49, −0.5, −0.55, −0.6, −0.65, −0.7, −0.75, −0.8, −0.85, −0.9, −0.95, −1, −1.1, −1.2, −1.3, −1.4, −1.5, −1.6, −1.7, −1.8, −1.9, −2, −2.1, −2.2, −2.3, −2.4, −2.5, −2.6, −2.7, −2.8, −2.9, −3, −3.1, −3.2, −3.3, −3.4, −3.5, −3.6, −3.7, −3.8, −3.9, −4, −4.1, −4.2, −4.3, −4.4, −4.5, −4.6, −4.7, −4.8, −4.9, −5, −5.5, −6, −6.5, −7, −7.5, −8, −8.5, −9, −9.5, −10, −11, −12, −13, −14, −15, −16, −17, −18, −19, −20 or less, can be classified as a loss.

In some embodiments, one algorithm can be used to call or identify significant genetic variations, wherein any segment whose median log 2 ratio was less than or equal to −0.1, −0.11, −0.12, −0.13, −0.14, −0.15, −0.16, −0.17, −0.18, −0.19, −0.2, −0.21, −0.22, −0.23, −0.24, −0.25, −0.26, −0.27, −0.28, −0.29, −0.3, −0.31, −0.32, −0.33, −0.34, −0.35, −0.36, −0.37, −0.38, −0.39, −0.4, −0.41, −0.42, −0.43, −0.44, −0.45, −0.46, −0.47, −0.48, −0.49, −0.5, −0.55, −0.6, −0.65, −0.7, −0.75, −0.8, −0.85, −0.9, −0.95, −1, −1.1, −1.2, −1.3, −1.4, −1.5, −1.6, −1.7, −1.8, −1.9, −2, −2.1, −2.2, −2.3, −2.4, −2.5, −2.6, −2.7, −2.8, −2.9, −3, −3.1, −3.2, −3.3, −3.4, −3.5, −3.6, −3.7, −3.8, −3.9, −4, −4.1, −4.2, −4.3, −4.4, −4.5, −4.6, −4.7, −4.8, −4.9, −5, −5.5, −6, −6.5, −7, −7.5, −8, −8.5, −9, −9.5, −10, −11, −12, −13, −14, −15, −16, −17, −18, −19, −20 or less, can be classified as a loss. For example, any CNV segment whose median log 2 ratio is less than −0.35 as determined by DNAcopy can be classified as a loss. For example, losses can be determined according to a threshold log 2 ratio, which can be set at -0.35. In another embodiment, losses can be determined according to a threshold log 2 ratio, which can be set at −0.5.

In some embodiments, two algorithms can be used to call or identify significant genetic variations, wherein any segment whose median log 2 ratio is less than or equal to −0.1, −0.11, −0.12, −0.13, −0.14, −0.15, −0.16, −0.17, −0.18, −0.19, −0.2, −0.21, −0.22, −0.23, −0.24, −0.25, −0.26, −0.27, −0.28, −0.29, −0.3, −0.31, −0.32, −0.33, −0.34, −0.35, −0.36, −0.37, −0.38, −0.39, −0.4, −0.41, −0.42, −0.43, −0.44, −0.45, −0.46, −0.47, −0.48, −0.49, −0.5, −0.55, −0.6, −0.65, −0.7, −0.75, −0.8, −0.85, −0.9, −0.95, −1, −1.1, −1.2, −1.3, −1.4, −1.5, −1.6, −1.7, −1.8, −1.9, −2, −2.1, −2.2, −2.3, −2.4, −2.5, −2.6, −2.7, −2.8, −2.9, −3, −3.1, −3.2, −3.3, −3.4, −3.5, −3.6, −3.7, −3.8, −3.9, −4, −4.1, −4.2, −4.3, −4.4, −4.5, −4.6, −4.7, −4.8, −4.9, −5, −5.5, −6, −6.5, −7, −7.5, −8, −8.5, −9, −9.5, −10, −11, −12, −13, −14, −15, −16, −17, −18, −19, −20 or less, as determined by one algorithm, and wherein any segment whose median log 2 ratio is less than or equal to −0.1, −0.11, −0.12, −0.13, −0.14, −0.15, −0.16, −0.17, −0.18, −0.19, −0.2, −0.21, −0.22, −0.23, −0.24, −0.25, −0.26, −0.27, −0.28, −0.29, −0.3, −0.31, −0.32, −0.33, −0.34, −0.35, −0.36, −0.37, −0.38, −0.39, −0.4, −0.41, −0.42, −0.43, −0.44, −0.45, −0.46, −0.47, −0.48, −0.49, −0.5, −0.55, −0.6, −0.65, −0.7, −0.75, −0.8, −0.85, −0.9, −0.95, −1, −1.1, −1.2, −1.3, −1.4, −1.5, −1.6, −1.7, −1.8, −1.9, −2, −2.1, −2.2, −2.3, −2.4, −2.5, −2.6, −2.7, −2.8, −2.9, −3, −3.1, −3.2, −3.3, −3.4, −3.5, −3.6, −3.7, −3.8, −3.9, −4, −4.1, −4.2, −4.3, −4.4, −4.5, −4.6, −4.7, −4.8, −4.9, −5, −5.5, −6, −6.5, −7, −7.5, −8, −8.5, −9, −9.5, −10, −11, −12, −13, −14, −15, −16, −17, −18, −19, −20, or less, as determined by the other algorithm can be classified as a loss. For example, CNV calling can comprise using the Aberration Detection Module 2 (ADM2) algorithm and the DNAcopy algorithm, wherein losses can be determined according to a two threshold log 2 ratios, wherein the Aberration Detection Module 2 (ADM2) algorithm log 2 ratio can be −0.25 and the DNAcopy algorithm log 2 ratio can be −0.41.

In some embodiments, the use of two algorithms to call or identify significant genetic variations can be a stringent method. In some embodiments, the use of two algorithms to call or identify significant genetic variations can be a more stringent method compared to the use of one algorithm to call or identify significant genetic variations.

In some embodiments, any CNV segment whose median log 2 ratio is greater than a log 2 ratio threshold value can be classified as a gain. For example, any segment whose median log 2 ratio is greater than 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, or more can be classified as a gain.

In some embodiments, one algorithm can be used to call or identify significant genetic variations, wherein any segment whose median log 2 ratio is greater than or equal to 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, or more can be classified as a gain. For example, any CNV segment whose median log 2 ratio is greater than 0.35 as determined by DNAcopy can be classified as a gain. For example, gains can be determined according to a threshold log 2 ratio, which can be set at 0.35. In another embodiment, gains can be determined according to a threshold log 2 ratio, which can be set at 0.5.

In some embodiments, two algorithms can be used to call or identify significant genetic variations, wherein any segment whose median log 2 ratio is greater than or equal to 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3 or more, as determined by one algorithm, and wherein any segment whose median log 2 ratio is greater than or equal to 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, or 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, or more, as determined by the other algorithm the can be classified as a gain. For example, CNV calling can comprise using the Aberration Detection Module 2 (ADM2) algorithm and the DNAcopy algorithm, wherein gains can be determined according to a two threshold log 2 ratios, wherein the Aberration Detection Module 2 (ADM2) algorithm log 2 ratio can be 0.25 and the DNAcopy algorithm log 2 ratio can be 0.32.

Any CNV segment whose absolute (median log-ratio/mad) value is less than 2 can be excluded (not identified as a significant genetic variation). For example, any CNV segment whose absolute (median log-ratio/mad) value is less than 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.6, or 0.5 or less can be excluded.

In some embodiments, multivariate analyses or joint risk analyses, including the use of multiplicative model for overall risk assessment, can subsequently be used to determine the overall risk conferred based on the genotype status at the multiple loci. Use of a multiplicative model, for example, assuming that the risk of individual risk variants multiply to establish the overall effect, allows for a straight-forward calculation of the overall risk for multiple markers. The multiplicative model is a parsimonious model that usually fits the data of complex traits reasonably well. Deviations from multiplicity have been rarely described in the context of common variants for common diseases, and if reported are usually only suggestive since very large sample sizes can be required to be able to demonstrate statistical interactions between loci. Assessment of risk based on such analysis can subsequently be used in the methods, uses and kits of the disclosure, as described herein.

In some embodiments, the significance of increased or decreased susceptibility can be measured by a percentage. In some embodiments, a significant increased susceptibility can be measured as a relative susceptibility of at least 1.2, including but not limited to: at least 1.3, at least 1.4, at least 1.5, at least 1.6, at least 1.7, at least 1.8, at least 1.9, at least 2.0, at least 2.5, at least 3.0, at least 4.0, at least 5.0, at least 6.0, at least 7.0, at least 8.0, at least 9.0, at least 10.0, and at least 15.0. In some embodiments, a relative susceptibility of at least 2.0, at least 3.0, at least 4.0, at least, 5.0, at least 6.0, or at least 10.0 is significant. Other values for significant susceptibility are also contemplated, for example, at least 2.5, 3.5, 4.5, 5.5, or any suitable other numerical values, wherein the values are also within scope of the present disclosure. In some embodiments, a significant increase in susceptibility is at least about 20%, including but not limited to about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, and 1500%. In one particular embodiment, a significant increase in susceptibility is at least 100%. In other embodiments, a significant increase in susceptibility is at least 200%, at least 300%, at least 400%, at least 500%, at least 700%, at least 800%, at least 900% and at least 1000%. Other cutoffs or ranges as deemed suitable by the person skilled in the art to characterize the disclosure are also contemplated, and those are also within scope of the present disclosure. In certain embodiments, a significant increase in susceptibility is characterized by a p-value, such as a p-value of less than 0.5, less than 0.4, less than 0.3, less than 0.2, less than 0.1, less than 0.05, less than 0.01, less than 0.001, less than 0.0001, less than 0.00001, less than 0.000001, less than 0.0000001, less than 0.00000001, or less than 0.000000001.

In some embodiments, an individual who is at a decreased susceptibility for or the lack of presence of a condition (e.g., PML) can be an individual in whom at least one genetic variation, conferring decreased susceptibility for or the lack of presence of the condition is identified. In some embodiments, the genetic variations conferring decreased susceptibility are also protective. In one aspect, the genetic variations can confer a significant decreased susceptibility of or lack of presence of PML.

In some embodiments, significant decreased susceptibility can be measured as a relative susceptibility of less than 0.9, including but not limited to less than 0.9, less than 0.8, less than 0.7, less than 0.6, less than 0.5, less than 0.4, less than 0.3, less than 0.2 and less than 0.1. In some embodiments, the decrease in susceptibility is at least 20%, including but not limited to at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% and at least 98%. Other cutoffs or ranges as deemed suitable by the person, skilled in the art to characterize the disclosure are however also contemplated, and those are also within scope of the present disclosure. In certain embodiments, a significant decrease in susceptibility is characterized by a p-value, such as a p-value of less than 0.05, less than 0.01, less than 0.001, less than 0.0001, less than 0.00001, less than 0.000001, less than 0.0000001, less than 0.00000001, or less than 0.000000001. Other tests for significance can be used, for example, a Fisher-exact test. Other statistical tests of significance known to the skilled person are also contemplated and are also within scope of the disclosure.

In some preferred embodiments, the significance of increased or decreased susceptibility can be determined according to the ratio of measurements from a test subject to a reference subject. In some embodiments, losses or gains of one or more CNVs can be determined according to a threshold log₂ ratio determined by these measurements. In some embodiments, a log₂ ratio value greater than 0.35, or 0.5, is indicative of a gain of one or more CNVs. In some embodiments, a log₂ ratio value less than −0.35, or −0.5, is indicative of a loss of one or more CNVs. In some embodiments, the ratio of measurements from a test subject to a reference subject may be inverted such that the log 2 ratios of copy number gains are negative and the log 2 ratios of copy number losses are positive.

In some embodiments, the combined or overall susceptibility associated with a plurality of variants associated with PML can also be assessed; for example, the genetic variations described herein to be associated with susceptibility to PML can be combined with other common genetic risk factors. Combined risk for such genetic variants can be estimated in an analogous fashion to the methods described herein.

Calculating risk conferred by a particular genotype for the individual can be based on comparing the genotype of the individual to previously determined risk expressed, for example, as a relative risk (RR) or an odds ratio (OR), for the genotype, for example, for a heterozygous carrier of an at-risk variant for PML. An odds ratio can be a statistical measure used as a metric of causality. For example, in genetic disease research it can be used to convey the significance of a variant in a disease cohort relative to an unaffected/normal cohort. The calculated risk for the individual can be the relative risk for a subject, or for a specific genotype of a subject, compared to the average population. The average population risk can be expressed as a weighted average of the risks of different genotypes, using results from a reference population, and the appropriate calculations to calculate the risk of a genotype group relative to the population can then be performed. Alternatively, the risk for an individual can be based on a comparison of particular genotypes, for example, heterozygous and/or homozygous carriers of an at-risk allele of a marker compared with non-carriers of the at-risk allele (or pair of alleles in the instance of compound heterozygous variants, wherein one variant impacts the maternally inherited allele and the other impacts the paternally inherited allele). Using the population average can, in certain embodiments, be more convenient, since it provides a measure that can be easy to interpret for the user, for example, a measure that gives the risk for the individual, based on his/her genotype, compared with the average in the population.

In some embodiments, the OR value can be calculated as follows: OR=(A/(N1−A))/(U/(N2−U)), where A=number of affected cases with variant, N1=total number of affected cases, U=number of unaffected cases with variant and N2=total number of unaffected cases. In circumstances where U=0, it is conventional to set U=1, so as to avoid infinities. In some preferred embodiments, the OR can be calculated essentially as above, except that where U or A=0, 0.5 is added to all of A, N1, U, N2. In another embodiment, a Fisher's Exact Test (FET) can be calculated using standard methods. In another embodiment, the p-values can be corrected for false discovery rate (FDR) using the Benjamini-Hochberg method (Benjamini Y. and Hochberg Y., J. Royal Statistical Society 57:289 (1995); Osborne J. A. and Barker C. A. (2007)).

In certain embodiments of the disclosure, a genetic variation is correlated to PML by referencing genetic variation data to a look-up table that comprises correlations between the genetic variation and PML. The genetic variation in certain embodiments comprises at least one indication of the genetic variation. In some embodiments, the table comprises a correlation for one genetic variation. In other embodiments, the table comprises a correlation for a plurality of genetic variations in both scenarios, by referencing to a look-up table that gives an indication of a correlation between a genetic variation and PML, a risk for PML, or a susceptibility to PML, can be identified in the individual from whom the nucleic acid sample is derived.

The present disclosure also pertains to methods of clinical screening, for example, diagnosis, prognosis, or theranosis of a subject performed by a medical professional using the methods disclosed herein. In other embodiments, the disclosure pertains to methods of screening performed by a layman. The layman can be a customer of a genotyping, microarray, exome sequencing, or whole genome sequencing service provider. The layman can also be a genotype, microarray, exome sequencing, or whole genome sequencing service provider, who performs genetic analysis on a DNA sample from an individual, in order to provide service related to genetic risk factors for particular traits or diseases, based on the genotype status of the subject obtained from use of the methods described herein. The resulting genotype or genetic information can be made available to the individual and can be compared to information about PML or risk of developing PML associated with one or various genetic variations, including but not limited to, information from public or private genetic variation databases or literature and scientific publications. The screening applications of PML-associated genetic variations, as described herein, can, for example, be performed by an individual, a health professional, or a third party, for example a service provider who interprets genotype information from the subject. In some embodiments the genetic analysis is performed in a CLIA-certified laboratory (e.g. the federal regulatory standards the U.S. that are specified in the Clinical Laboratory Improvement Amendments, administered by the Centers for Medicare and Medicaid Services) or equivalent laboratories in Europe and elsewhere in the world.

The information derived from analyzing sequence data can be communicated to any particular body, including the individual from which the nucleic acid sample or sequence data is derived, a guardian or representative of the individual, clinician, research professional, medical professional, service provider, and medical insurer or insurance company. Medical professionals can be, for example, doctors, nurses, medical laboratory technologists, and pharmacists. Research professionals can be, for example, principle investigators, research technicians, postdoctoral trainees, and graduate students.

In some embodiments, a professional can be assisted by determining whether specific genetic variants are present in a nucleic acid sample from a subject, and communicating information about genetic variants to a professional. After information about specific genetic variants is reported, a medical professional can take one or more actions that can affect subject care. For example, a medical professional can record information in the subject's medical record (e.g., electronic health record or electronic medical record, including, but not limited to, country-scale health services such as the National Health Service in the United Kingdom) regarding the subject's risk of developing PML. In some embodiments, a medical professional can record information regarding risk assessment, or otherwise transform the subject's medical record, to reflect the subject's current medical condition. In some embodiments, a medical professional can review and evaluate a subject's entire medical record and assess multiple treatment strategies for clinical intervention of a subject's condition. In another embodiment, information can be recorded in the context of the system developed by the World Health Organization (WHO), the International Statistical Classification of Diseases and Related Health Problems (ICD), which is currently using the 10th revision (ICD-10 codes). For example, the ICD-10 code for PML is A81.2, whereas the ICD-10 code for multiple sclerosis is G35.

A medical professional can initiate or modify treatment after receiving information regarding a subject's screening for PML, for example. In some embodiments, a medical professional can recommend a change in therapy or exclude a therapy. In some embodiments, a medical professional can enroll a subject in a clinical trial for, by way of example, detecting correlations between a haplotype as described herein and any measurable or quantifiable parameter relating to the outcome of the treatment as described above.

In some embodiments, a medical professional can communicate information regarding a subject's screening of developing PML to a subject or a subject's family. In some embodiments, a medical professional can provide a subject and/or a subject's family with information regarding PML and risk assessment information, including treatment options, and referrals to specialists. In some embodiments, a medical professional can provide a copy of a subject's medical records to a specialist. In some embodiments, a research professional can apply information regarding a subject's risk of developing PML to advance scientific research. In some embodiments, a research professional can obtain a subject's haplotype as described herein to evaluate a subject's enrollment, or continued participation, in a research study or clinical trial. In some embodiments, a research professional can communicate information regarding a subject's screening of PML to a medical professional. In some embodiments, a research professional can refer a subject to a medical professional.

Any appropriate method can be used to communicate information to another person. For example, information can be given directly or indirectly to a professional and a laboratory technician can input a subject's genetic variation as described herein into a computer-based record. In some embodiments, information is communicated by making a physical alteration to medical or research records. For example, a medical professional can make a permanent notation or flag a medical record for communicating the risk assessment to other medical professionals reviewing the record. In addition, any type of communication can be used to communicate the risk assessment information. For example, mail, e-mail, telephone, and face-to-face interactions can be used. The information also can be communicated to a professional by making that information electronically available to the professional. For example, the information can be communicated to a professional by placing the information on a computer database such that the professional can access the information. In addition, the information can be communicated to a hospital, clinic, or research facility serving as an agent for the professional.

Results of these tests, and optionally interpretive information, can be returned to the subject, the health care provider or to a third party. The results can be communicated to the tested subject, for example, with a prognosis and optionally interpretive materials that can help the subject understand the test results and prognosis; used by a health care provider, for example, to determine whether to administer a specific drug, or whether a subject should be assigned to a specific category, for example, a category associated with a specific disease endophenotype, or with drug response or non-response; used by a third party such as a healthcare payer, for example, an insurance company or HMO, or other agency, to determine whether or not to reimburse a health care provider for services to the subject, or whether to approve the provision of services to the subject. For example, the healthcare payer can decide to reimburse a health care provider for treatments for PML if the subject has PML or has an increased risk of developing PML.

Also provided herein are databases that include a list of genetic variations as described herein, and wherein the list can be largely or entirely limited to genetic variations identified as useful for screening PML as described herein. The list can be stored, for example, on a flat file or computer-readable medium. The databases can further include information regarding one or more subjects, for example, whether a subject is affected or unaffected, clinical information such as endophenotype, age of onset of symptoms, any treatments administered and outcomes, for example, data relevant to pharmacogenomics, diagnostics, prognostics or theranostics, and other details, for example, data about the disorder in the subject, or environmental (e.g., including, but not limited to, infection or a history of infection with HIV or JCV) or other genetic factors. The databases can be used to detect correlations between a particular haplotype and the information regarding the subject.

The methods described herein can also include the generation of reports for use, for example, by a subject, care giver, or researcher, that include information regarding a subject's genetic variations, and optionally further information such as treatments administered, treatment history, medical history, predicted response, and actual response. The reports can be recorded in a tangible medium, e.g., a computer-readable disk, a solid state memory device, or an optical storage device.

Methods of Screening using Variations in RNA and/or Polypeptides

In some embodiments of the disclosure, screening of PML can be made by examining or comparing changes in expression, localization, binding partners, and composition of a polypeptide encoded by a nucleic acid variant associated with PML, for example, in those instances where the genetic variations of the present disclosure results in a change in the composition or expression of the polypeptide and/or RNA, for example, mRNAs, microRNAs (miRNAs), and other noncoding RNAs (ncRNAs). Thus, screening of PML can be made by examining expression and/or composition of one of these polypeptides and/or RNA, or another polypeptide and/or RNA encoded by a nucleic acid associated with PML, in those instances where the genetic variation of the present disclosure results in a change in the expression, localization, binding partners, and/or composition of the polypeptide and/or RNA. In some embodiments, screening can comprise diagnosing a subject. In some embodiments, screening can comprise determining a prognosis of a subject, for example determining the susceptibility of developing PML. In some embodiments, screening can comprise theranosing a subject.

The genetic variations described herein that show association to PML can play a role through their effect on one or more of these genes, either by directly impacting one or more genes or influencing the expression of one or more nearby genes. For example, while not intending to be limited by theory, it is generally expected that a deletion of a chromosomal segment comprising a particular gene, or a fragment of a gene, can either result in an altered composition or expression, or both, of the encoded polypeptide and/or mRNA. Likewise, duplications, or high number copy number variations, are in general expected to result in increased expression of encoded polypeptide and/or RNA if the gene they are expressed from is fully encompassed within the duplicated (or triplicated, or even higher copy number gains) genomic segment, or conversely can result in decreased expression or a disrupted RNA or polypeptide if one or both breakpoints of the copy number gain disrupt a given gene. Other possible mechanisms affecting genes within a genetic variation region include, for example, effects on transcription, effects on RNA splicing, alterations in relative amounts of alternative splice forms of mRNA, effects on RNA stability, effects on transport from the nucleus to cytoplasm, and effects on the efficiency and accuracy of translation. Thus, DNA variations can be detected directly, using the subjects unamplified or amplified genomic DNA, or indirectly, using RNA or DNA obtained from the subject's tissue(s) that are present in an aberrant form or expression level as a result of the genetic variations of the disclosure showing association to PML. In another embodiment, DNA variations can be detected indirectly using a polypeptide or protein obtained from the subject's tissue(s) that is present in an aberrant form or expression level as a result of genetic variations of the disclosure showing association to the PML. In another embodiment, an aberrant form or expression level of a polypeptide or protein that results from one or more genetic variations of the disclosure showing association to PML can be detected indirectly via another polypeptide or protein present in the same biological/cellular pathway that is modulated or interacts with said polypeptide or protein that results from one or more genetic variations of the disclosure. In some embodiments, the genetic variations of the disclosure showing association to PML can affect the expression of a gene within the genetic variation region. In some embodiments, a genetic variation affecting an exonic region of a gene can affect, disrupt, or modulate the expression of the gene. In some embodiments, a genetic variation affecting an intronic or intergenic region of a gene can affect, disrupt, or modulate the expression of the gene.

Certain genetic variation regions can have flanking duplicated segments, and genes within such segments can have altered expression and/or composition as a result of such genomic alterations. Regulatory elements affecting gene expression can be located far away, even as far as tens or hundreds of kilobases away, from the gene that is regulated by said regulatory elements. Thus, in some embodiments, regulatory elements for genes that are located outside the gene (e.g., upstream or downstream of the gene) can be located within the genetic variation, and thus be affected by the genetic variation. It is thus contemplated that the detection of the genetic variations described herein, can be used for assessing expression for one or more of associated genes not directly impacted by the genetic variations. In some embodiments, a genetic variation affecting an intergenic region of a gene can affect, disrupt, or modulate the expression of a gene located elsewhere in the genome, such as described above. For example, a genetic variation affecting an intergenic region of a gene can affect, disrupt, or modulate the expression of a transcription factor, located elsewhere in the genome, which regulates the gene. Regulatory elements can also be located within a gene, such as within intronic regions, and similarly impact the expression level of the gene and ultimately the protein expression level without changing the structure of the protein. The effects of genetic variants on regulatory elements can manifest in a tissue-specific manner; for example, one or more transcription factors that bind to the regulatory element that is impacted by one or more genetic variations may be expressed at higher concentration in neurons as compared to skin cells (e.g., the impact of the one or more genetic variations may be primarily evident in neuronal cells).

In some embodiments, genetic variations of the disclosure showing association to PML can affect protein expression at the translational level. It can be appreciated by those skilled in the art that this can occur by increased or decreased expression of one or more microRNAs (miRNAs) that regulates expression of a protein known to be important, or implicated, in the cause, onset, or progression of PML. Increased or decreased expression of the one or more miRNAs can result from gain or loss of the whole miRNA gene, disruption or impairment of a portion of the gene (e.g., by an indel or CNV), or even a single base change (SNP or SNV) that produces an altered, non-functional or aberrant functioning miRNA sequence. It can also be appreciated by those skilled in the art that the expression of protein, for example, one known to cause PML by increased or decreased expression, can result due to a genetic variation that results in alteration of an existing miRNA binding site within the polypeptide's mRNA transcript, or even creates a new miRNA binding site that leads to aberrant polypeptide expression.

A variety of methods can be used for detecting polypeptide composition and/or expression levels, including but not limited to enzyme linked immunosorbent assays (ELISA), Western blots, spectroscopy, mass spectrometry, peptide arrays, colorimetry, electrophoresis, isoelectric focusing, immunoprecipitations, immunoassays, and immunofluorescence and other methods well-known in the art. A test nucleic acid sample from a subject can be assessed for the presence of an alteration in the expression and/or an alteration in composition of the polypeptide encoded by a nucleic acid associated with PML. An “alteration” in the polypeptide expression or composition, as used herein, refers to an alteration in expression or composition in a test nucleic acid sample, as compared to the expression or composition of the polypeptide in a control nucleic acid sample. Such alteration can, for example, be an alteration in the quantitative polypeptide expression or can be an alteration in the qualitative polypeptide expression, for example, expression of a mutant polypeptide or of a different splicing variant, or a combination thereof. In some embodiments, screening of PML can be made by detecting a particular splicing variant encoded by a nucleic acid associated with PML, or a particular pattern of splicing variants.

Antibodies can be polyclonal or monoclonal and can be labeled or unlabeled. An intact antibody or a fragment thereof can be used. The term “labeled”, with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled as previously described herein. Other non-limiting examples of indirect labeling include detection of a primary antibody using a labeled secondary antibody, for example, a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin.

Methods of Detecting Genetic Variations

In some embodiments, standard techniques for genotyping for the presence genetic variations, for example, amplification, can be used. Amplification of nucleic acids can be accomplished using methods known in the art. Generally, sequence information from the region of interest can be used to design oligonucleotide primers that can be identical or similar in sequence to opposite strands of a template to be amplified. In some embodiments, amplification methods can include but are not limited to, fluorescence-based techniques utilizing PCR, for example, ligase chain reaction (LCR), Nested PCR, transcription amplification, self-sustained sequence replication, nucleic acid based sequence amplification (NASBA), and multiplex ligation-dependent probe amplification (MLPA). Guidelines for selecting primers for PCR amplification are well known in the art. In some embodiments, a computer program can be used to design primers, for example, Oligo (National Biosciences, Inc, Plymouth Minn.), MacVector (Kodak/IBI), and GCG suite of sequence analysis programs.

In some embodiments, commercial methodologies available for genotyping, for example, SNP genotyping, can be used, but are not limited to, TaqMan genotyping assays (Applied Biosystems), SNPlex platforms (Applied Biosystems), gel electrophoresis, capillary electrophoresis, size exclusion chromatography, mass spectrometry, for example, MassARRAY system (Sequenom), minisequencing methods, real-time Polymerase Chain Reaction (PCR), Bio-Plex system (BioRad), CEQ and SNPstream systems (Beckman), array hybridization technology, for example, Affymetrix GeneChip (Perlegen), BeadArray Technologies, for example, Illumina GoldenGate and Infinium assays, array tag technology, Multiplex Ligation-dependent Probe Amplification (MLPA), and endonuclease-based fluorescence hybridization technology (Invader assay, either using unamplified or amplified genomic DNA, or unamplified total RNA, or unamplified or amplified cDNA; Third Wave/Hologic). PCR can be a procedure in which target nucleic acid is amplified in a manner similar to that described in U.S. Pat. No. 4,683,195 and subsequent modifications of the procedure described therein. PCR can include a three phase temperature cycle of denaturation of DNA into single strands, annealing of primers to the denatured strands, and extension of the primers by a thermostable DNA polymerase enzyme. This cycle can be repeated so that there are enough copies to be detected and analyzed. In some embodiments, real-time quantitative PCR can be used to determine genetic variations, wherein quantitative PCR can permit both detection and quantification of a DNA sequence in a nucleic acid sample, for example, as an absolute number of copies or as a relative amount when normalized to DNA input or other normalizing genes. In some embodiments, methods of quantification can include the use of fluorescent dyes that can intercalate with double-stranded DNA, and modified DNA oligonucleotide probes that can fluoresce when hybridized with a complementary DNA.

In some embodiments of the disclosure, a nucleic acid sample obtained from the subject can be collected and PCR can be used to amplify a fragment of nucleic acid that comprises one or more genetic variations that can be indicative of a susceptibility to PML. In some embodiments, detection of genetic variations can be accomplished by expression analysis, for example, by using quantitative PCR. In some embodiments, this technique can assess the presence or absence of a genetic alteration in the expression or composition of one or more polypeptides or splicing variants encoded by a nucleic acid associated with PML.

In some embodiments, the nucleic acid sample from a subject containing a SNP can be amplified by PCR prior to detection with a probe. In such an embodiment, the amplified DNA serves as the template for a detection probe and, in some embodiments, an enhancer probe. Certain embodiments of the detection probe, the enhancer probe, and/or the primers used for amplification of the template by PCR can comprise the use of modified bases, for example, modified A, T, C, G, and U, wherein the use of modified bases can be useful for adjusting the melting temperature of the nucleotide probe and/or primer to the template DNA, In some embodiments, modified bases are used in the design of the detection nucleotide probe. Any modified base known to the skilled person can be selected in these methods, and the selection of suitable bases is well within the scope of the skilled person based on the teachings herein and known bases available from commercial sources as known to the skilled person.

In some embodiments, identification of genetic variations can be accomplished using hybridization methods. The presence of a specific marker allele or a particular genomic segment comprising a genetic variation, or representative of a genetic variation, can be indicated by sequence-specific hybridization of a nucleic acid probe specific for the particular allele or the genetic variation in a nucleic acid sample that has or has not been amplified but methods described herein. The presence of more than one specific marker allele or several genetic variations can be indicated by using two or more sequence-specific nucleic acid probes, wherein each is specific for a particular allele and/or genetic variation.

Hybridization can be performed by methods well known to the person skilled in the art, for example, hybridization techniques such as fluorescent in situ hybridization (FISH), Southern analysis, Northern analysis, or in situ hybridization. In some embodiments, hybridization refers to specific hybridization, wherein hybridization can be performed with no mismatches. Specific hybridization, if present, can be using standard methods. In some embodiments, if specific hybridization occurs between a nucleic acid probe and the nucleic acid in the nucleic acid sample, the nucleic acid sample can contain a sequence that can be complementary to a nucleotide present in the nucleic acid probe. In some embodiments, if a nucleic acid probe can contain a particular allele of a polymorphic marker, or particular alleles for a plurality of markers, specific hybridization is indicative of the nucleic acid being completely complementary to the nucleic acid probe, including the particular alleles at polymorphic markers within the probe. In some embodiments a probe can contain more than one marker alleles of a particular haplotype, for example, a probe can contain alleles complementary to 2, 3, 4, 5 or all of the markers that make up a particular haplotype. In some embodiments detection of one or more particular markers of the haplotype in the nucleic acid sample is indicative that the source of the nucleic acid sample has the particular haplotype.

In some embodiments, PCR conditions and primers can be developed that amplify a product only when the variant allele is present or only when the wild type allele is present, for example, allele-specific PCR. In some embodiments of allele-specific PCR, a method utilizing a detection oligonucleotide probe comprising a fluorescent moiety or group at its 3′ terminus and a quencher at its 5′ terminus, and an enhancer oligonucleotide, can be employed (see e.g., Kutyavin et al., Nucleic Acid Res. 34:e128 (2006)).

An allele-specific primer/probe can be an oligonucleotide that is specific for particular a polymorphism can be prepared using standard methods. In some embodiments, allele-specific oligonucleotide probes can specifically hybridize to a nucleic acid region that contains a genetic variation. In some embodiments, hybridization conditions can be selected such that a nucleic acid probe can specifically bind to the sequence of interest, for example, the variant nucleic acid sequence.

In some embodiments, allele-specific restriction digest analysis can be used to detect the existence of a polymorphic variant of a polymorphism, if alternate polymorphic variants of the polymorphism can result in the creation or elimination of a restriction site. Allele-specific restriction digests can be performed, for example, with the particular restriction enzyme that can differentiate the alleles. In some embodiments, PCR can be used to amplify a region comprising the polymorphic site, and restriction fragment length polymorphism analysis can be conducted. In some embodiments, for sequence variants that do not alter a common restriction site, mutagenic primers can be designed that can introduce one or more restriction sites when the variant allele is present or when the wild type allele is present.

In some embodiments, fluorescence polarization template-directed dye-terminator incorporation (FP-TDI) can be used to determine which of multiple polymorphic variants of a polymorphism can be present in a subject. Unlike the use of allele-specific probes or primers, this method can employ primers that can terminate adjacent to a polymorphic site, so that extension of the primer by a single nucleotide can result in incorporation of a nucleotide complementary to the polymorphic variant at the polymorphic site.

In some embodiments, DNA containing an amplified portion can be dot-blotted, using standard methods and the blot contacted with the oligonucleotide probe. The presence of specific hybridization of the probe to the DNA can then be detected. The methods can include determining the genotype of a subject with respect to both copies of the polymorphic site present in the genome, wherein if multiple polymorphic variants exist at a site, this can be appropriately indicated by specifying which variants are present in a subject. Any of the detection means described herein can be used to determine the genotype of a subject with respect to one or both copies of the polymorphism present in the subject's genome.

In some embodiments, a peptide nucleic acid (PNA) probe can be used in addition to, or instead of, a nucleic acid probe in the methods described herein. A PNA can be a DNA mimic having a peptide-like, inorganic backbone, for example, N-(2-aminoethyl) glycine units with an organic base (A, G, C, T or U) attached to the glycine nitrogen via a methylene carbonyl linker.

Nucleic acid sequence analysis can also be used to detect genetic variations, for example, genetic variations can be detected by sequencing exons, introns, 5′ untranslated sequences, or 3′ untranslated sequences. One or more methods of nucleic acid analysis that are available to those skilled in the art can be used to detect genetic variations, including but not limited to, direct manual sequencing, automated fluorescent sequencing, single-stranded conformation polymorphism assays (SSCP); clamped denaturing gel electrophoresis (CDGE); denaturing gradient gel electrophoresis (DGGE), two-dimensional gel electrophoresis (2DGE or TDGE); conformational sensitive gel electrophoresis (CSGE); denaturing high performance liquid chromatography (DHPLC), infrared matrix-assisted laser desorption/ionization (IR-MALDI) mass spectrometry, mobility shift analysis, quantitative real-time PCR, restriction enzyme analysis, heteroduplex analysis; chemical mismatch cleavage (CMC), RNase protection assays, use of polypeptides that recognize nucleotide mismatches, allele-specific PCR, real-time pyrophosphate DNA sequencing, PCR amplification in combination with denaturing high performance liquid chromatography (dHPLC), and combinations of such methods.

Sequencing can be accomplished through classic Sanger sequencing methods, which are known in the art. In some embodiments sequencing can be performed using high-throughput sequencing methods some of which allow detection of a sequenced nucleotide immediately after or upon its incorporation into a growing strand, for example, detection of sequence in substantially real time or real time. In some cases, high throughput sequencing generates at least 1,000, at least 5,000, at least 10,000, at least 20,000, at least 30,000, at least 40,000, at least 50,000, at least 100,000 or at least 500,000 sequence reads per hour; with each read being at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 120 or at least 150 bases per read (or 500-1,000 bases per read for 454).

High-throughput sequencing methods can include but are not limited to, Massively Parallel Signature Sequencing (MPSS, Lynx Therapeutics), Polony sequencing, 454 pyrosequencing, Illumina (Solexa) sequencing, Illumina (Solexa) sequencing using 10× Genomics library preparation, SOLiD sequencing, on semiconductor sequencing, DNA nanoball sequencing, Helioscope™ single molecule sequencing, Single Molecule SMRT™ sequencing, Single Molecule real time (RNAP) sequencing, Nanopore DNA sequencing, and/or sequencing by hybridization, for example, a non-enzymatic method that uses a DNA microarray, or microfluidic Sanger sequencing.

In some embodiments, high-throughput sequencing can involve the use of technology available by Helicos BioSciences Corporation (Cambridge, Mass.) such as the Single Molecule Sequencing by Synthesis (SMSS) method. SMSS is unique because it allows for sequencing the entire human genome in up to 24 hours. This fast sequencing method also allows for detection of a SNP/nucleotide in a sequence in substantially real time or real time. Finally, SMSS is powerful because, like the MIP technology, it does not use a pre-amplification step prior to hybridization. SMSS does not use any amplification. SMSS is described in US Publication Application Nos. 20060024711; 20060024678; 20060012793; 20060012784; and 20050100932. In some embodiments, high-throughput sequencing involves the use of technology available by 454 Life Sciences, Inc. (a Roche company, Branford, Conn.) such as the PicoTiterPlate device which includes a fiber optic plate that transmits chemiluminescent signal generated by the sequencing reaction to be recorded by a CCD camera in the instrument. This use of fiber optics allows for the detection of a minimum of 20 million base pairs in 4.5 hours.

In some embodiments, PCR-amplified single-strand nucleic acid can be hybridized to a primer and incubated with a polymerase, ATP sulfurylase, luciferase, apyrase, and the substrates luciferin and adenosine 5′ phosphosulfate. Next, deoxynucleotide triphosphates corresponding to the bases A, C, G, and T (U) can be added sequentially. A base incorporation can be accompanied by release of pyrophosphate, which can be converted to ATP by sulfurylase, which can drive synthesis of oxyluciferin and the release of visible light. Since pyrophosphate release can be equimolar with the number of incorporated bases, the light given off can be proportional to the number of nucleotides adding in any one step. The process can repeat until the entire sequence can be determined. In some embodiments, pyrosequencing can be utilized to analyze amplicons to determine whether breakpoints are present. In some embodiments, pyrosequencing can map surrounding sequences as an internal quality control.

Pyrosequencing analysis methods are known in the art. Sequence analysis can include a four-color sequencing by ligation scheme (degenerate ligation), which involves hybridizing an anchor primer to one of four positions. Then an enzymatic ligation reaction of the anchor primer to a population of degenerate nonamers that are labeled with fluorescent dyes can be performed. At any given cycle, the population of nonamers that is used can be structured such that the identity of one of its positions can be correlated with the identity of the fluorophore attached to that nonamer. To the extent that the ligase discriminates for complementarily at that queried position, the fluorescent signal can allow the inference of the identity of the base. After performing the ligation and four-color imaging, the anchor primer: nonamer complexes can be stripped and a new cycle begins. Methods to image sequence information after performing ligation are known in the art.

In some embodiments, analysis by restriction enzyme digestion can be used to detect a particular genetic variation if the genetic variation results in creation or elimination of one or more restriction sites relative to a reference sequence. In some embodiments, restriction fragment length polymorphism (RFLP) analysis can be conducted, wherein the digestion pattern of the relevant DNA fragment indicates the presence or absence of the particular genetic variation in the nucleic acid sample.

In some embodiments, arrays of oligonucleotide probes that can be complementary to target nucleic acid sequence segments from a subject can be used to identify genetic variations. In some embodiments, an array of oligonucleotide probes comprises an oligonucleotide array, for example, a microarray. In some embodiments, the present disclosure features arrays that include a substrate having a plurality of addressable areas, and methods of using them. At least one area of the plurality includes a nucleic acid probe that binds specifically to a sequence comprising a genetic variation, and can be used to detect the absence or presence of the genetic variation, for example, one or more SNPs, microsatellites, or CNVs, as described herein, to determine or identify an allele or genotype. For example, the array can include one or more nucleic acid probes that can be used to detect a genetic variation associated with a gene and/or gene product. In some embodiments, the array can further comprise at least one area that includes a nucleic acid probe that can be used to specifically detect another marker associated with PML as described herein.

Microarray hybridization can be performed by hybridizing a nucleic acid of interest, for example, a nucleic acid encompassing a genetic variation, with the array and detecting hybridization using nucleic acid probes. In some embodiments, the nucleic acid of interest is amplified prior to hybridization. Hybridization and detecting can be carried out according to standard methods described in Published PCT Applications: WO 92/10092 and WO 95/11995, and U.S. Pat. No. 5,424,186. For example, an array can be scanned to determine the position on the array to which the nucleic acid hybridizes. The hybridization data obtained from the scan can be, for example, in the form of fluorescence intensities as a function of location on the array.

Arrays can be formed on substrates fabricated with materials such as paper; glass; plastic, for example, polypropylene, nylon, or polystyrene; polyacrylamide; nitrocellulose; silicon; optical fiber; or any other suitable solid or semisolid support; and can be configured in a planar, for example, glass plates or silicon chips); or three dimensional, for example, pins, fibers, beads, particles, microtiter wells, and capillaries, configuration.

Methods for generating arrays are known in the art and can include for example; photolithographic methods (U.S. Pat. Nos. 5,143,854, 5,510,270 and 5,527,681); mechanical methods, for example, directed-flow methods (U.S. Pat. No. 5,384,261); pin-based methods (U.S. Pat. No. 5,288,514); bead-based techniques (PCT US/93/04145); solid phase oligonucleotide synthesis methods; or by other methods known to a person skilled in the art (see, e.g., Bier, F. F., et al., Adv Biochem Eng Biotechnol 109:433-53 (2008); Hoheisel, J. D., Nat Rev Genet 7: 200-10 (2006); Fan, J. B., et al., Methods Enzymol 410:57-73 (2006); Raqoussis, J. & Elvidge, G., Expert Rev Mol Design 6: 145-52 (2006); Mockler, T. C., et al., Genomics 85: 1-15 (2005), and references cited therein, the entire teachings of each of which are incorporated by reference herein). Many additional descriptions of the preparation and use of oligonucleotide arrays for detection of polymorphisms can be found, for example, in U.S. Pat. Nos. 6,858,394, 6,429,027, 5,445,934, 5,700,637, 5,744,305, 5,945,334, 6,054,270, 6,300,063, 6,733,977, 7,364,858, EP 619 321, and EP 373 203, the entire teachings of which are incorporated by reference herein. Methods for array production, hybridization, and analysis are also described in Snijders et al., Nat. Genetics 29:263-264 (2001); Klein et al., Proc. Natl. Acad. Sci. USA 96:4494-4499 (1999); Albertson et al., Breast Cancer Research and Treatment 78:289-298 (2003); and Snijders et al., “BAC microarray based comparative genomic hybridization,” in: Zhao et al., (eds), Bacterial Artificial Chromosomes: Methods and Protocols, Methods in Molecular Biology, Humana Press (2002).

In some embodiments, oligonucleotide probes forming an array can be attached to a substrate by any number of techniques, including, but not limited to, in situ synthesis, for example, high-density oligonucleotide arrays, using photolithographic techniques; spotting/printing a medium to low density on glass, nylon, or nitrocellulose; by masking; and by dot-blotting on a nylon or nitrocellulose hybridization membrane. In some embodiments, oligonucleotides can be immobilized via a linker, including but not limited to, by covalent, ionic, or physical linkage. Linkers for immobilizing nucleic acids and polypeptides, including reversible or cleavable linkers, are known in the art (U.S. Pat. No. 5,451,683 and WO98/20019). In some embodiments, oligonucleotides can be non-covalently immobilized on a substrate by hybridization to anchors, by means of magnetic beads, or in a fluid phase, for example, in wells or capillaries.

An array can comprise oligonucleotide hybridization probes capable of specifically hybridizing to different genetic variations. In some embodiments, oligonucleotide arrays can comprise a plurality of different oligonucleotide probes coupled to a surface of a substrate in different known locations. In some embodiments, oligonucleotide probes can exhibit differential or selective binding to polymorphic sites, and can be readily designed by one of ordinary skill in the art, for example, an oligonucleotide that is perfectly complementary to a sequence that encompasses a polymorphic site, for example, a sequence that includes the polymorphic site, within it, or at one end, can hybridize preferentially to a nucleic acid comprising that sequence, as opposed to a nucleic acid comprising an alternate polymorphic variant.

In some embodiments, arrays can include multiple detection blocks, for example, multiple groups of probes designed for detection of particular polymorphisms. In some embodiments, these arrays can be used to analyze multiple different polymorphisms. In some embodiments, detection blocks can be grouped within a single array or in multiple, separate arrays, wherein varying conditions, for example, conditions optimized for particular polymorphisms, can be used during hybridization. General descriptions of using oligonucleotide arrays for detection of polymorphisms can be found, for example, in U.S. Pat. Nos. 5,858,659 and 5,837,832. In addition to oligonucleotide arrays, cDNA arrays can be used similarly in certain embodiments.

The methods described herein can include but are not limited to providing an array as described herein; contacting the array with a nucleic acid sample, and detecting binding of a nucleic acid from the nucleic acid sample to the array. In some embodiments, the method can comprise amplifying nucleic acid from the nucleic acid sample, for example, a region associated with PML or a region that includes another region associated with PML. In some embodiments, the methods described herein can include using an array that can identify differential expression patterns or copy numbers of one or more genes in nucleic acid samples from control and affected individuals. For example, arrays of probes to a marker described herein can be used to identify genetic variations between DNA from an affected subject, and control DNA obtained from an individual that does not have PML. Since the nucleotides on the array can contain sequence tags, their positions on the array can be accurately known relative to the genomic sequence.

In some embodiments, it can be desirable to employ methods that can detect the presence of multiple genetic variations, for example, polymorphic variants at a plurality of polymorphic sites, in parallel or substantially simultaneously. In some embodiments, these methods can comprise oligonucleotide arrays and other methods, including methods in which reactions, for example, amplification and hybridization, can be performed in individual vessels, for example, within individual wells of a multi-well plate or other vessel.

Determining the identity of a genetic variation can also include or consist of reviewing a subject's medical history, where the medical history includes information regarding the identity, copy number, presence or absence of one or more alleles or SNPs in the subject, e.g., results of a genetic test.

In some embodiments extended runs of homozygosity (ROH) may be useful to map recessive disease genes in outbred populations. Furthermore, even in complex disorders, a high number of affected individuals may have the same haplotype in the region surrounding a disease mutation. Therefore, a rare pathogenic variant and surrounding haplotype can be enriched in frequency in a group of affected individuals compared with the haplotype frequency in a cohort of unaffected controls. Homozygous haplotypes (HH) that are shared by multiple affected individuals can be important for the discovery of recessive disease genes in a condition such as PML. In some embodiments, the traditional homozygosity mapping method can be extended by analyzing the haplotype within shared ROH regions to identify homozygous segments of identical haplotype that are present uniquely or at a higher frequency in PML probands compared to parental controls. Such regions are termed risk homozygous haplotypes (rHH), which may contain low-frequency recessive variants that contribute to PML risk in a subset of PML patients.

Genetic variations can also be identified using any of a number of methods well known in the art. For example, genetic variations available in public databases, which can be searched using methods and custom algorithms or algorithms known in the art, can be used. In some embodiments, a reference sequence can be from, for example, the human draft genome sequence, publicly available in various databases, or a sequence deposited in a database such as GenBank.

A comparison of one or more genomes relative to one or more other genomes with array CGH, or a variety of other genetic variation detection methods, can reveal the set of genetic variations between two genomes, between one genome in comparison to multiple genomes, or between one set of genomes in comparison to another set of genomes. In some embodiments, an array CGH experiment can be performed by hybridizing a single test genome against a pooled nucleic acid sample of two or more genomes, which can result in minimizing the detection of higher frequency variants in the experiment. In some embodiments, a test genome can be hybridized alone (e.g., one-color detection) to a microarray, for example, using array CGH or SNP genotyping methods, and the comparison step to one or more reference genomes can be performed in silico to reveal the set of genetic variations in the test genome relative to the one or more reference genomes. In one embodiment, a single test genome is compared to a single reference genome in a 2-color experiment wherein both genomes are cohybridized to the microarray. In some embodiments, the whole genome or whole exome from one or more subjects is analyzed. In some embodiments, nucleic acid information has already been obtained for the whole genome or whole exome from one or more individuals and the nucleic acid information is obtained from in silico analysis.

Any of the polynucleotides described, including polynucleotides comprising a genetic variation, can be made synthetically using methods known in the art.

Methods of Detecting CNVs

Detection of genetic variations, specifically CNVs, can be accomplished by one or more suitable techniques described herein. Generally, techniques that can selectively determine whether a particular chromosomal segment is present or absent in an individual can be used for genotyping CNVs. Identification of novel copy number variations can be done by methods for assessing genomic copy number changes.

In some embodiments, methods include but are not limited to, methods that can quantitatively estimate the number of copies of a particular genomic segment, but can also include methods that indicate whether a particular segment is present in a nucleic acid sample or not. In some embodiments, the technique to be used can quantify the amount of segment present, for example, determining whether a DNA segment is deleted, duplicated, or triplicated in subject, for example, Fluorescent In Situ Hybridization (FISH) techniques, and other methods described herein. In some embodiments, methods include detection of copy number variation from array intensity and sequencing read depth using a stepwise Bayesian model (Zhang, et al., BMC Bioinformatics, 11:539 (2010)). In some embodiments, methods include detecting copy number variations using shotgun sequencing, CNV-seq (Xie C., et al., BMC Bioinformatics, 10:80 (2009)). In some embodiments, methods include analyzing next-generation sequencing (NGS) data for CNV detection using any one of several algorithms developed for each of the four broad methods for CNV detection using NGS, namely the depth of coverage (DOC), read-pair (RP), split-read (SR) and assembly-based (AS) methods. (Teo et al., Bioinformatics (2012)). In some embodiments, methods include combining coverage with map information for the identification of deletions and duplications in targeted sequence data (Nord et al., BMC Genomics, 12:184 (2011)).

In some embodiments, other genotyping technologies can be used for detection of CNVs, including but not limited to, karyotype analysis, Molecular Inversion Probe array technology, for example, Affymetrix SNP Array 6.0, and BeadArray Technologies, for example, Illumina GoldenGate and Infinium assays, as can other platforms such as NimbleGen HD2.1 or HD4.2, High-Definition Comparative Genomic Hybridization (CGH) arrays (Agilent Technologies), tiling array technology (Affymetrix), multiplex ligation-dependent probe amplification (MLPA), Invader assay, fluorescence in situ hybridization, and, in one embodiment, Array Comparative Genomic Hybridization (aCGH) methods. As described herein, karyotype analysis can be a method to determine the content and structure of chromosomes in a nucleic acid sample. In some embodiments, karyotyping can be used, in lieu of aCGH, to detect translocations or inversions, which can be copy number neutral, and, therefore, not detectable by aCGH. Information about amplitude of particular probes, which can be representative of particular alleles, can provide quantitative dosage information for the particular allele, and by consequence, dosage information about the CNV in question, since the marker can be selected as a marker representative of the CNV and can be located within the CNV. In some embodiments, if the CNV is a deletion, the absence of particular marker allele is representative of the deletion. In some embodiments, if the CNV is a duplication or a higher order copy number variation, the signal intensity representative of the allele correlating with the CNV can represent the copy number. A summary of methodologies commonly used is provided in Perkel (Perkel J. Nature Methods 5:447-453 (2008)).

PCR assays can be utilized to detect CNVs and can provide an alternative to array analysis. In particular, PCR assays can enable detection of precise boundaries of gene/chromosome variants, at the molecular level, and which boundaries are identical in different individuals. PCR assays can be based on the amplification of a junction fragment present only in individuals that carry a deletion. This assay can convert the detection of a loss by array CGH to one of a gain by PCR.

Examples of PCR techniques that can be used in the present disclosure include, but are not limited to quantitative PCR, real-time quantitative PCR (qPCR), quantitative fluorescent PCR (QF-PCR), multiplex fluorescent PCR (MF-PCR), real time PCR (RT-PCR), single cell PCR, PCR-RFLP/RT-PCR-RFLP, hot start PCR and Nested PCR. Other suitable amplification methods include the ligase chain reaction (LCR), ligation mediated PCR (LM-PCR), degenerate oligonucleotide probe PCR (DOP-PCR), transcription amplification, self-sustained sequence replication, selective amplification of target polynucleotide sequences, consensus sequence primed polymerase chain reaction (CP-PCR), arbitrarily primed polymerase chain reaction (AP-PCR) and nucleic acid sequence based amplification (NASBA).

Alternative methods for the simultaneous interrogation of multiple regions include quantitative multiplex PCR of short fluorescent fragments (QMPSF), multiplex amplifiable probe hybridization (MAPH) and multiplex ligation-dependent probe amplification (MLPA), in which copy-number differences for up to 40 regions can be scored in one experiment. Another approach can be to specifically target regions that harbor known segmental duplications, which are often sites of copy-number variation. By targeting the variable nucleotides between two copies of a segmental duplication (called paralogous sequence variants) using a SNP-genotyping method that provides independent fluorescence intensities for the two alleles, it is possible to detect an increase in intensity of one allele compared with the other.

In some embodiments, the amplified piece of DNA can be bound to beads using the sequencing element of the nucleic acid tag under conditions that favor a single amplified piece of DNA molecule to bind a different bead and amplification occurs on each bead. In some embodiments, such amplification can occur by PCR. Each bead can be placed in a separate well, which can be a picoliter-sized well. In some embodiments, each bead is captured within a droplet of a PCR-reaction-mixture-in-oil-emulsion and PCR amplification occurs within each droplet. The amplification on the bead results in each bead carrying at least one million, at least 5 million, or at least 10 million copies of the single amplified piece of DNA molecule.

In embodiments where PCR occurs in oil-emulsion mixtures, the emulsion droplets are broken, the DNA is denatured and the beads carrying single-stranded nucleic acids clones are deposited into a well, such as a picoliter-sized well, for further analysis according to the methods described herein. These amplification methods allow for the analysis of genomic DNA regions. Methods for using bead amplification followed by fiber optics detection are described in Margulies et al., Nature, 15; 437(7057):376-80 (2005), and as well as in US Publication Application Nos. 20020012930; 20030068629; 20030100102; 20030148344; 20040248161; 20050079510, 20050124022; and 20060078909.

Another variation on the array-based approach can be to use the hybridization signal intensities that are obtained from the oligonucleotides employed on Affymetrix SNP arrays or in Illumina Bead Arrays. Here hybridization intensities are compared with average values that are derived from controls, such that deviations from these averages indicate a change in copy number. As well as providing information about copy number, SNP arrays have the added advantage of providing genotype information. For example, they can reveal loss of heterozygosity, which could provide supporting evidence for the presence of a deletion, or might indicate segmental uniparental disomy (which can recapitulate the effects of structural variation in some genomic regions—Prader-Willi and Angelman syndromes, for example).

Many of the basic procedures followed in microarray-based genome profiling are similar, if not identical, to those followed in expression profiling and SNP analysis, including the use of specialized microarray equipment and data-analysis tools. Since microarray-based expression profiling has been well established in the last decade, much can be learned from the technical advances made in this area. Examples of the use of microarrays in nucleic acid analysis that can be used are described in U.S. Pat. Nos. 6,300,063, 5,837,832, 6,969,589, 6,040,138, 6,858,412, U.S. application Ser. No. 08/529,115, U.S. application Ser. No. 10/272,384, U.S. application Ser. No. 10/045,575, U.S. application Ser. No. 10/264,571 and U.S. application Ser. No. 10/264,574. It should be noted that there are also distinct differences such as target and probe complexity, stability of DNA over RNA, the presence of repetitive DNA and the need to identify single copy number alterations in genome profiling.

In some embodiments, the genetic variations detected comprise CNVs and can be detected using array CGH. In some embodiments, array CGH can be been implemented using a wide variety of techniques. The initial approaches used arrays produced from large-insert genomic clones such as bacterial artificial chromosomes (BACs). Producing sufficient BAC DNA of adequate purity to make arrays is arduous, so several techniques to amplify small amounts of starting material have been employed. These techniques include ligation-mediated PCR (Snijders et al., Nat. Genet. 29:263-64), degenerate primer PCR using one or several sets of primers, and rolling circle amplification. BAC arrays that provide complete genome tiling paths are also available. Arrays made from less complex nucleic acids such as cDNAs, selected PCR products, and oligonucleotides can also be used. Although most CGH procedures employ hybridization with total genomic DNA, it is possible to use reduced complexity representations of the genome produced by PCR techniques. Computational analysis of the genome sequence can be used to design array elements complementary to the sequences contained in the representation. Various SNP genotyping platforms, some of which use reduced complexity genomic representations, can be useful for their ability to determine both DNA copy number and allelic content across the genome. In some embodiments, small amounts of genomic DNA can be amplified with a variety of whole genome or whole exome amplification methods prior to CGH analysis of the nucleic acid sample. A “whole exome,” as used herein, includes exons throughout the whole genome that are expressed in genes. Since exon selection has tissue and cell type specificity, these positions may be different in the various cell types resulting from a splice variant or alternative splicing. A “whole genome,” as used herein, includes the entire genetic code of a genome.

The different basic approaches to array CGH provide different levels of performance, so some are more suitable for particular applications than others. The factors that determine performance include the magnitudes of the copy number changes, their genomic extents, the state and composition of the specimen, how much material is available for analysis, and how the results of the analysis can be used. Many applications use reliable detection of copy number changes of much less than 50%, a more stringent requirement than for other microarray technologies. Note that technical details are extremely important and different implementations of methods using the same array CGH approach can yield different levels of performance. Various CGH methods are known in the art and are equally applicable to one or more methods of the present disclosure. For example, CGH methods are disclosed in U.S. Pat. Nos. 7,030,231; 7,011,949; 7,014,997; 6,977,148; 6,951,761; and 6,916,621, the disclosure from each of which is incorporated by reference herein in its entirety.

The data provided by array CGH are quantitative measures of DNA sequence dosage. Array CGH provides high-resolution estimates of copy number aberrations, and can be performed efficiently on many nucleic acid samples. The advent of array CGH technology makes it possible to monitor DNA copy number changes on a genomic scale and many projects have been launched for studying the genome in specific diseases.

In some embodiments, whole genome array-based comparative genome hybridization (array CGH) analysis, or array CGH on a subset of genomic regions, can be used to efficiently interrogate human genomes for genomic imbalances at multiple loci within a single assay. The development of comparative genomic hybridization (CGH) (Kallioniemi et al., Science 258: 818-21 (1992)) provided the first efficient approach to scanning entire genomes for variations in DNA copy number. The importance of normal copy number variation involving large segments of DNA has been unappreciated. Array CGH is a breakthrough technique in human genetics, which is attracting interest from clinicians working in fields as diverse as cancer and IVF (In Vitro Fertilization). The use of CGH microarrays in the clinic holds great promise for identifying regions of genomic imbalance associated with disease. Advances from identifying chromosomal critical regions associated with specific phenotypes to identifying the specific dosage sensitive genes can lead to therapeutic opportunities of benefit to patients. Array CGH is a specific, sensitive and rapid technique that can enable the screening of the whole genome in a single test. It can facilitate and accelerate the screening process in human genetics and is expected to have a profound impact on the screening and counseling of patients with genetic disorders. It is now possible to identify the exact location on the chromosome where an aberration has occurred and it is possible to map these changes directly onto the genomic sequence.

An array CGH approach provides a robust method for carrying out a genome-wide scan to find novel copy number variants (CNVs). The array CGH methods can use labeled fragments from a genome of interest, which can be competitively hybridized with a second differentially labeled genome to arrays that are spotted with cloned DNA fragments, revealing copy-number differences between the two genomes. Genomic clones (for example, BACs), cDNAs, PCR products and oligonucleotides, can all be used as array targets. The use of array CGH with BACs was one of the earliest employed methods and is popular, owing to the extensive coverage of the genome it provides, the availability of reliable mapping data and ready access to clones. The last of these factors is important both for the array experiments themselves, and for confirmatory FISH experiments.

In a typical CGH measurement, total genomic DNA is isolated from control and reference subjects, differentially labeled, and hybridized to a representation of the genome that allows the binding of sequences at different genomic locations to be distinguished. More than two genomes can be compared simultaneously with suitable labels. Hybridization of highly repetitive sequences is typically suppressed by the inclusion of unlabeled Cot-1 DNA in the reaction. In some embodiments of array CGH, it is beneficial to mechanically shear the genomic DNA in a nucleic acid sample, for example, with sonication, prior to its labeling and hybridization step. In another embodiment, array CGH may be performed without use of Cot-1 DNA or a sonication step in the preparation of the genomic DNA in a nucleic acid sample. The relative hybridization intensity of the test and reference signals at a given location can be proportional to the relative copy number of those sequences in the test and reference genomes. If the reference genome is normal then increases and decreases in signal intensity ratios directly indicate DNA copy number variation within the genome of the test cells. Data are typically normalized so that the modal ratio for the genome is set to some standard value, typically 1.0 on a linear scale or 0.0 on a logarithmic scale. Additional measurements such as FISH or flow cytometry can be used to determine the actual copy number associated with a ratio level.

In some embodiments, an array CGH procedure can include the following steps. First, large-insert clones, for example, BACs can be obtained from a supplier of clone libraries. Then, small amounts of clone DNA can be amplified, for example, by degenerate oligonucleotide-primed (DOP) PCR or ligation-mediated PCR in order to obtain sufficient quantities needed for spotting. Next, PCR products can be spotted onto glass slides using, for example, microarray robots equipped with high-precision printing pins. Depending on the number of clones to be spotted and the space available on the microarray slide, clones can either be spotted once per array or in replicate. Repeated spotting of the same clone on an array can increase precision of the measurements if the spot intensities are averaged, and allows for a detailed statistical analysis of the quality of the experiments. Subject and control DNAs can be labeled, for example, with either Cy3 or Cy5-dUTP using random priming and can be subsequently hybridized onto the microarray in a solution containing an excess of Cot1-DNA to block repetitive sequences. Hybridizations can either be performed manually under a coverslip, in a gasket with gentle rocking or, automatically using commercially available hybridization stations. These automated hybridization stations can allow for an active hybridization process, thereby improving the reproducibility as well as reducing the actual hybridization time, which increases throughput. The hybridized DNAs can be detected through the two different fluorochromes using standard microarray scanning equipment with either a scanning confocal laser or a charge coupled device (CCD) camera-based reader, followed by spot identification using commercially or freely available software packages.

The use of CGH with arrays that comprise long oligonucleotides (60-100 bp) can improve the detection resolution (in some embodiments, as small as ˜3-5 kb sized CNVs on arrays designed for interrogation of human whole genomes) over that achieved using BACs (limited to 50-100 kb or larger sized CNVs due to the large size of BAC clones). In some embodiments, the resolution of oligonucleotide CGH arrays is achieved via in situ synthesis of 1-2 million unique features/probes per microarray, which can include microarrays available from Roche NimbleGen and Agilent Technologies. In addition to array CGH methods for copy number detection, other embodiments for partial or whole genome analysis of CNVs within a genome include, but are not limited to, use of SNP genotyping microarrays and sequencing methods.

Another method for copy number detection that uses oligonucleotides can be representational oligonucleotide microarray analysis (ROMA). It is similar to that applied in the use of BAC and CGH arrays, but to increase the signal-to-noise ratio, the ‘complexity’ of the input DNA is reduced by a method called representation or whole-genome sampling. Here the DNA that is to be hybridized to the array can be treated by restriction digestion and then ligated to adapters, which results in the PCR-based amplification of fragments in a specific size-range. As a result, the amplified DNA can make up a fraction of the entire genomic sequence—that is, it is a representation of the input DNA that has significantly reduced complexity, which can lead to a reduction in background noise. Other suitable methods available to the skilled person can also be used, and are within scope of the present disclosure.

A comparison of one or more genomes relative to one or more other genomes with array CGH, or a variety of other CNV detection methods, can reveal the set of CNVs between two genomes, between one genome in comparison to multiple genomes, or between one set of genomes in comparison to another set of genomes. In some embodiments, an array CGH experiment can be performed by hybridizing a single test genome against a pooled nucleic acid sample of two or more genomes, which can result in minimizing the detection of higher frequency variants in the experiment. In some embodiments, a test genome can be hybridized alone (e.g. one-color detection) to a microarray, for example, using array CGH or SNP genotyping methods, and the comparison step to one or more reference genomes can be performed in silico to reveal the set of CNVs in the test genome relative to the one or more reference genomes. In one preferred embodiment, a single test genome is compared to a single reference genome in a 2-color experiment wherein both genomes are cohybridized to the microarray.

Array CGH can be used to identify genes that are causative or associated with a particular phenotype, condition, or disease by comparing the set of CNVs found in the affected cohort to the set of CNVs found in an unaffected cohort. An unaffected cohort may consist of any individual unaffected by the phenotype, condition, or disease of interest, but in one preferred embodiment is comprised of individuals or subjects that are apparently healthy (normal). Methods employed for such analyses are described in U.S. Pat. Nos. 7,702,468 and 7,957,913. In some embodiments, candidate genes that are causative or associated (e.g., a biomarker) with a phenotype, condition, or disease will be identified by CNVs that occur in the affected cohort but not in the unaffected cohort. In some embodiments, candidate genes that are causative or associated (e.g., a biomarker) with a phenotype, condition, or disease will be identified by CNVs that occur at a statistically significant higher frequency in the affected cohort as compared their frequency in the unaffected cohort. Thus, CNVs preferentially detected in the affected cohort as compared to the unaffected cohort can serve as beacons of genes that are causative or associated with a particular phenotype, condition, or disease. Methods employed for such analyses are described in U.S. Pat. No. 8,862,410. In some embodiments, CNV detection and comparison methods can result in direct identification of the gene that is causative or associated with phenotype, condition, or disease if the CNVs are found to overlap with or encompass the gene(s). In some embodiments, CNV detection and comparison methods can result in identification of regulatory regions of the genome (e.g., promoters, enhancers, transcription factor binding sites) that regulate the expression of one or more genes that are causative or associated with the phenotype, condition, or disease of interest. In some embodiments, CNV detection and comparison methods can result in identification of a region in the genome in linkage disequilibrium with a genetic variant that is causative or associated with the phenotype, condition, or disease of interest. In another embodiment, CNV detection and comparison methods can result in identification of a region in the genome in linkage disequilibrium with a genetic variant that is protective against the condition or disease of interest.

Due to the large amount of genetic variation between any two genomes, or two sets (cohorts) of genomes, being compared, one preferred embodiment is to reduce the genetic variation search space by interrogating only CNVs, as opposed to the full set of genetic variants that can be identified in an individual's genome or exome. The set of CNVs that occur only, or at a statistically higher frequency, in the affected cohort as compared to the unaffected cohort can then be further investigated in targeted sequencing experiments to reveal the full set of genetic variants (of any size or type) that are causative or associated (e.g., a biomarker) with a phenotype, condition, or disease. It can be appreciated to those skilled in the art that the targeted sequencing experiments are performed in both the affected and unaffected cohorts in order to identify the genetic variants (e.g., SNVs and indels) that occur only, or at a statistically significant higher frequency, in the affected individual or cohort as compared to the unaffected cohort. Methods employed for such analyses are described in U.S. Pat. No. 8,862,410.

A method of screening a subject for a disease or disorder can comprise assaying a nucleic acid sample from the subject to detect sequence information for more than one genetic locus and comparing the sequence information to a panel of nucleic acid biomarkers and screening the subject for the presence or absence of the disease or disorder if one or more of low frequency biomarkers in the panel are present in the sequence information.

The panel can comprise at least one nucleic acid biomarker (e.g., genetic variation) for each of the more than one genetic loci. For example, the panel can comprise 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100, 150, 200 or more nucleic acid biomarkers for each of the more than one genetic locus. In some embodiments, the panel can comprise from about 2-1000 nucleic acid biomarkers. For example, the panel can comprise from about 2-900, 2-800, 2-700, 2-600, 2-500, 2-400, 2-300, 2-200, 2-100, 25-900, 25-800, 25-700, 25-600, 25-500, 25-400, 25-300, 25-200, 25-100, 100-1000, 100-900, 100-800, 100-700, 100-600, 100-500, 100-400, 100-300, 100-200, 200-1000, 200-900, 200-800, 200-700, 200-600, 200-500, 200-400, 200-300, 300-1000, 300-900, 300-800, 300-700, 300-600, 300-500, 300-400, 400-1000, 400-900, 400-800, 400-700, 400-600, 400-500, 500-1000, 500-900, 500-800, 500-700, 500-600, 600-1000, 600-900, 600-800, 600-700, 700-1000, 700-900, 700-800, 800-1000, 800-900, or 900-1000 nucleic acid biomarkers.

In some embodiments, a biomarker (e.g., genetic variation) can occur at a frequency of 1% or more in a population of subjects without the disease or disorder. For example, a biomarker can occur at a frequency of 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or more in a population of subjects without the disease or disorder. In some embodiments, a biomarker can occur at a frequency from about 1%-20% in a population of subjects without the disease or disorder. For example, a biomarker can occur at a frequency of from about 1%-5% or 1%-10%, in a population of subjects without the disease or disorder.

The panel can comprise at least 2 low frequency biomarkers (e.g., low frequency genetic variations). For example, the panel can comprise at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 3, 14, 15, 15, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 250, 500, or 1000 or more low frequency biomarkers. In some embodiments, the panel can comprise from about 2-1000 low frequency biomarkers. For example, the panel can comprise from about 2-900, 2-800, 2-700, 2-600, 2-500, 2-400, 2-300, 2-200, 2-100, 25-900, 25-800, 25-700, 25-600, 25-500, 25-400, 25-300, 25-200, 25-100, 100-1000, 100-900, 100-800, 100-700, 100-600, 100-500, 100-400, 100-300, 100-200, 200-1000, 200-900, 200-800, 200-700, 200-600, 200-500, 200-400, 200-300, 300-1000, 300-900, 300-800, 300-700, 300-600, 300-500, 300-400, 400-1000, 400-900, 400-800, 400-700, 400-600, 400-500, 500-1000, 500-900, 500-800, 500-700, 500-600, 600-1000, 600-900, 600-800, 600-700, 700-1000, 700-900, 700-800, 800-1000, 800-900, or 900-1000 low frequency biomarkers.

In some embodiments, a low frequency biomarker can occur at a frequency of 1% or less in a population of subjects without the disease or disorder. For example, a low frequency biomarker can occur at a frequency of 0.5%, 0.1%, 0.05%, 0.01%, 0.005%, 0.001%, 0.0005%, or 0.0001% or less in a population of subjects without the disease or disorder. In some embodiments, a low frequency biomarker can occur at a frequency from about 0.0001%-0.1% in a population of subjects without the disease or disorder. For example, a low frequency biomarker can occur at a frequency of from about 0.0001%-0.0005%, 0.0001%-0.001%, 0.0001%-0.005%, 0.0001%-0.01%, 0.0001%-0.05%, 0.0001%-0.1%, 0.0001%-0.5%, 0.0005%-0.001%, 0.0005%-0.005%, 0.0005%-0.01%, 0.0005%-0.05%, 0.0005%-0.1%, 0.0005%-0.5%, 0.0005%-1%, 0.001%-0.005%, 0.001%-0.01%, 0.001%-0.05%, 0.001%-0.1%, 0.001%-0.5%, 0.001%-1%, 0.005%-0.01%, 0.005%-0.05%, 0.005%-0.1%, 0.005%-0.5%, 0.005%-1%, 0.01%-0.05%, 0.01%-0.1%, 0.01%-0.5%, 0.01%-1%, 0.05%-0.1%, 0.05%-0.5%, 0.05%-1%, 0.1%-0.5%, 0.1%-1%, or 0.5%-1% in a population of subjects without the disease or disorder. In another embodiment, genetic biomarker frequencies can range higher (e.g., 0.5% to 5%) and have utility for diagnostic testing or drug development targeting the genes that harbor such variants. Genetic variants of appreciable frequency and phenotypic effect in the general population are sometimes described as goldilocks variants (e.g., see Cohen J Clin Lipidol. 2013 May-June; 7(3 Suppl):S1-5 and Price et al. Am J Hum Genet. 2010 Jun. 11; 86(6):832-8).

In some embodiments, the presence or absence of the disease or disorder in the subject can be determined with at least 50% confidence. For example, the presence or absence of the disease or disorder in the subject can be determined with at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% confidence. In some embodiments, the presence or absence of the disease or disorder in the subject can be determined with a 50%-100% confidence. For example, the presence or absence of the disease or disorder in the subject can be determined with a 60%-100%, 70%-100%, 80%-100%, 90%-100%, 50%-90%, 50%-80%, 50%-70%, 50%-60%, 60%-90%, 60%-80%, 60%-70%, 70%-90%, 70%-80%, or 80%-90%. In one embodiment, PML candidate CNVs and genes or regulatory loci associated with these CNVs can be determined or identified by comparing genetic data from a cohort of normal individuals to that of an individual or a cohort of individuals known to have, or be susceptible to PML.

In one embodiment, PML candidate CNV-subregions and genes associated with these regions can be determined or identified by comparing genetic data from a cohort of normal individuals, such as a pre-existing database of CNVs found in normal individuals termed the Normal Variation Engine (NVE), to that of a cohort of individual known to have, or be susceptible to PML.

In some embodiments, a nucleic acid sample from one individual or nucleic acid samples from a pool of 2 or more individuals without PML can serve as the reference nucleic acid sample(s) and the nucleic acid sample from an individual known to have PML or being tested to determine if they have PML can serve as the test nucleic acid sample. In one preferred embodiment, the reference and test nucleic acid samples are sex-matched and co-hybridized on the CGH array. For example, reference nucleic acid samples can be labeled with a fluorophore such as Cy5, using methods described herein, and test subject nucleic acid samples can be labeled with a different fluorophore, such as Cy3. After labeling, nucleic acid samples can be combined and can be co-hybridized to a microarray and analyzed using any of the methods described herein, such as aCGH. Arrays can then be scanned and the data can be analyzed with software. Genetic alterations, such as CNVs, can be called using any of the methods described herein. A list of the genetic alterations, such as CNVs, can be generated for one or more test subjects and/or for one or more reference subjects. Such lists of CNVs can be used to generate a master list of non-redundant CNVs and/or CNV-subregions for each type of cohort. In one embodiment, a cohort of test nucleic acid samples, such as individuals known to have or suspected to have PML, can be cohybridized with an identical sex-matched reference individual or sex-matched pool of reference individuals to generate a list of redundant or non-redundant CNVs. Such lists can be based on the presence or absence of one or more CNVs and/or CNV subregions present in individuals within the cohort. In this manner, a master list can contain a number of distinct CNVs and/or CNV-subregions, some of which are uniquely present in a single individual and some of which are present in multiple individuals.

In some embodiments, CNVs and/or CNV-subregions of interest can be obtained by annotation of each CNV and/or CNV-subregion with relevant information, such as overlap with known genes and/or exons or intergenic regulatory regions such as transcription factor binding sites. In some embodiments, CNVs and/or CNV-subregions of interest can be obtained by calculating the OR for a CNV and/or CNV-subregion according to the following formula: OR=(PML/((# individuals in PML cohort)−PML))/(NVE/((# individuals in NVE cohort)—NVE)), where: PML=number of PML individuals with a CNV-subregion of interest and NVE=number of NVE subjects with the CNV-subregion of interest. If NVE=0, it can be set to 1 to avoid dealing with infinities in cases where no CNVs are seen in the NVE. In some embodiments, a set of publicly available CNVs (e.g., the Database of Genomic Variants) can be used as the Normal cohort for comparison to the affected cohort CNVs. In another embodiment, the set of Normal cohort CNVs may comprise a private database generated by the same CNV detection method, such as array CGH, or by a plurality of CNV detection methods that include, but are not limited to, array CGH, SNP genotyping arrays, custom CGH arrays, custom genotyping arrays, exome sequencing, whole genome sequencing, targeted sequencing, FISH, q-PCR, or MLPA.

The number of individuals in any given cohort can be at least about 10, 50, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2500, 5000, 7500, 10,000, 100,000, or more. In some embodiments, the number of individuals in any given cohort can be from 25-900, 25-800, 25-700, 25-600, 25-500, 25-400, 25-300, 25-200, 25-100, 100-1000, 100-900, 100-800, 100-700, 100-600, 100-500, 100-400, 100-300, 100-200, 200-1000, 200-900, 200-800, 200-700, 200-600, 200-500, 200-400, 200-300, 300-1000, 300-900, 300-800, 300-700, 300-600, 300-500, 300-400, 400-1000, 400-900, 400-800, 400-700, 400-600, 400-500, 500-1000, 500-900, 500-800, 500-700, 500-600, 600-1000, 600-900, 600-800, 600-700, 700-1000, 700-900, 700-800, 800-1000, 800-900, or 900-1000.

In some embodiments, a method of determining relevance or statistical significance of a genetic variant in a human subject to a disease or a condition associated with a genotype comprising screening a genome of a human subject with the disease or condition, such as by array Comparative Genomic Hybridization, sequencing, or SNP genotyping, to provide information on one or more genetic variants, such as those in Tables 1 and 2. The method can further comprise comparing, such as via a computer, information of said one or more genetic variants from the genome of said subject to a compilation of data comprising frequencies of genetic variants in at least 100 normal human subjects, such as those without the disease or condition. The method can further comprise determining a statistical significance or relevance of said one or more genetic variants from said comparison to the condition or disease or determining whether a genetic variant is present in said human subject but not present in said compilation of data from said comparison, or an algorithm can be used to call or identify significant genetic variations, such as a genetic variation whose median log 2 ratio is above or below a computed value. A computer can comprise computer executable logic that provides instructions for executing said comparison.

Different categories for CNVs of interest can be defined. In some embodiments, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions occur within intergenic regions and are associated with an OR of at least 0.7. For example, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions occur within intergenic regions and are associated with an OR of at least 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 175, or more. In some embodiments, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions occur within intergenic regions and are associated with an OR from about 0.7-200, 0.7-200, 0.7-90, 0.7-80, 0.7-70, 0.7-60, 0.7-50, 0.7-40, 0.7-30, 0.7-20, 0.7-10, 0.7-5, 10-200, 10-180, 10-160, 10-140, 10-120, 10-100, 10-80, 10-60, 10-40, 10-20, 20-200, 20-180, 20-160, 20-140, 20-120, 20-100, 20-80, 20-60, 20-40, 30-200, 30-180, 30-160, 30-140, 30-120, 30-100, 30-80, 30-60, 30-40, 40-200, 40-180, 40-160, 40-140, 40-120, 40-100, 40-90, 40-80, 40-70, 40-60, 40-50, 50-200, 50-180, 50-160, 50-140, 50-120, 50-100, 50-90, 50-80, 50-70, 50-60, 60-200, 60-180, 60-160, 60-140, 60-120, 60-100, 60-90, 60-80, 60-70, 70-200, 70-180, 70-160, 70-140, 70-120, 70-100, 70-90, 70-80, 80-200, 80-180, 80-160, 80-140, 80-120, 80-100, 80-90, 90-200, 90-180, 90-160, 90-140, 90-120, or 90-100.

In some embodiments, CNVs/CNV-subregions can be of interest if the CNV/CNV-subregion overlaps a known gene, and is associated with an OR of at least 1.8. For example, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions occur within intergenic regions and are associated with an OR of at least 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 175, or more. In some embodiments, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions occur within exonic regions and are associated with an OR from about 1.8-200, 1.8-200, 1.8-90, 1.8-80, 1.8-70, 1.8-60, 1.8-50, 1.8-40, 1.8-30, 1.8-20, 1.8-10, 1.8-5, 10-200, 10-180, 10-160, 10-140, 10-120, 10-100, 10-80, 10-60, 10-40, 10-20, 20-200, 20-180, 20-160, 20-140, 20-120, 20-100, 20-80, 20-60, 20-40, 30-200, 30-180, 30-160, 30-140, 30-120, 30-100, 30-80, 30-60, 30-40, 40-200, 40-180, 40-160, 40-140, 40-120, 40-100, 40-90, 40-80, 40-70, 40-60, 40-50, 50-200, 50-180, 50-160, 50-140, 50-120, 50-100, 50-90, 50-80, 50-70, 50-60, 60-200, 60-180, 60-160, 60-140, 60-120, 60-100, 60-90, 60-80, 60-70, 70-200, 70-180, 70-160, 70-140, 70-120, 70-100, 70-90, 70-80, 80-200, 80-180, 80-160, 80-140, 80-120, 80-100, 80-90, 90-200, 90-180, 90-160, 90-140, 90-120, or 90-100.

In some embodiments, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions are overlapping and/or non-overlapping, impact an exon, and they affect 1 or more PML cases but only 0 Normal subjects. In some embodiments, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions are overlapping and/or non-overlapping, impact an exon, and they affect 2 or more PML cases but only 0 or 1 Normal subjects. In some embodiments, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions are overlapping and/or non-overlapping, impact an exon, and they affect 1-5 PML cases but only 0 or 1 Normal subjects. For example, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions are overlapping and/or non-overlapping, impact an exon, and they affect 1 PML case but only 0 or 1 Normal subjects. This can enable identification of rarer CNVs in cases with PML. In some embodiments, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions are overlapping and/or non-overlapping, impact an exon, and they affect 1 PML case but only 0 or 1 Normal subjects, and are associated with an OR greater than 0.7, such as 1.8. In some embodiments, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions are overlapping and/or non-overlapping, impact an exon, and they affect 2 PML cases but only 0 or 1 Normal subjects. In some embodiments, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions are overlapping and/or non-overlapping, impact an exon, and they affect 3 PML cases but only 0 or 1 Normal subjects. In some embodiments, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions are overlapping and/or non-overlapping, impact an exon, and they affect 4 PML cases but only 0 or 1 Normal subjects.

In some embodiments, CNVs/CNV-subregions can be of interest if the OR associated with the sum of PML cases and the sum of NVE subjects affecting the same gene (including distinct CNVs/CNV-subregions) is at least 0.67. For example, a CNV/CNV-subregion can be of interest if the OR associated with the sum of PML cases and the sum of NVE subjects affecting the same gene (including distinct CNVs/CNV-subregions) is at least 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 175, or more. In some embodiments, a CNVs/CNV-subregions can be of interest if the OR associated with the sum of PML cases and the sum of NVE subjects affecting the same gene (including distinct CNVs/CNV-subregions) is from about 0.7-200, 0.7-200, 0.7-90, 0.7-80, 0.7-70, 0.7-60, 0.7-50, 0.7-40, 0.7-30, 0.7-20, 0.7-10, 0.7-5, 10-200, 10-180, 10-160, 10-140, 10-120, 10-100, 10-80, 10-60, 10-40, 10-20, 20-200, 20-180, 20-160, 20-140, 20-120, 20-100, 20-80, 20-60, 20-40, 30-200, 30-180, 30-160, 30-140, 30-120, 30-100, 30-80, 30-60, 30-40, 40-200, 40-180, 40-160, 40-140, 40-120, 40-100, 40-90, 40-80, 40-70, 40-60, 40-50, 50-200, 50-180, 50-160, 50-140, 50-120, 50-100, 50-90, 50-80, 50-70, 50-60, 60-200, 60-180, 60-160, 60-140, 60-120, 60-100, 60-90, 60-80, 60-70, 70-200, 70-180, 70-160, 70-140, 70-120, 70-100, 70-90, 70-80, 80-200, 80-180, 80-160, 80-140, 80-120, 80-100, 80-90, 90-200, 90-180, 90-160, 90-140, 90-120, or 90-100.

In some embodiments, CNVs/CNV-subregions can be of interest if the OR associated with the sum of PML cases and the sum of NVE subjects affecting the same gene (including distinct CNVs/CNV-subregions) is at least 1.8. For example, a CNV/CNV-subregion can be of interest if the OR associated with the sum of PML cases and the sum of NVE subjects affecting the same gene (including distinct CNVs/CNV-subregions) is at least 1.8, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 175, or more. In some embodiments, a CNVs/CNV-subregions can be of interest if the OR associated with the sum of PML cases and the sum of NVE subjects affecting the same gene (including distinct CNVs/CNV-subregions) is from about 1.8-200, 1.8-200, 1.8-90, 1.8-80, 1.8-70, 1.8-60, 1.8-50, 1.8-40, 1.8-30, 1.8-20, 1.8-10, 1.8-5, 10-200, 10-180, 10-160, 10-140, 10-120, 10-100, 10-80, 10-60, 10-40, 10-20, 20-200, 20-180, 20-160, 20-140, 20-120, 20-100, 20-80, 20-60, 20-40, 30-200, 30-180, 30-160, 30-140, 30-120, 30-100, 30-80, 30-60, 30-40, 40-200, 40-180, 40-160, 40-140, 40-120, 40-100, 40-90, 40-80, 40-70, 40-60, 40-50, 50-200, 50-180, 50-160, 50-140, 50-120, 50-100, 50-90, 50-80, 50-70, 50-60, 60-200, 60-180, 60-160, 60-140, 60-120, 60-100, 60-90, 60-80, 60-70, 70-200, 70-180, 70-160, 70-140, 70-120, 70-100, 70-90, 70-80, 80-200, 80-180, 80-160, 80-140, 80-120, 80-100, 80-90, 90-200, 90-180, 90-160, 90-140, 90-120, or 90-100.

In some embodiments, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions do not overlap (distinct CNV/CNV-subregion), but impact the same gene (or regulatory locus) and are associated with an OR of at least 6 (Genic (distinct CNV-subregions); OR>6). For example, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions do not overlap, but impact the same gene (or regulatory locus), and are associated with an OR of at 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, or more. In some embodiments, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions do not overlap, but impact the same gene (or regulatory locus), and are associated with an OR from about 6-100, 6-50, 6-40, 6-30, 6-20, 6-10, 6-9, 6-8, 6-7, 8-100, 8-50, 8-40, 8-30, 8-20, 8-10, 10-100, 10-50, 10-40, 10-30, 10-20, 20-100, 20-50, 20-40, 20-30, 30-100, 30-50, 30-40, 40-100, 40-50, 50-100, or 5-7. The CNV-subregion/gene can be an exonic or intronic part of the gene, or both.

In some embodiments, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions do not overlap a known gene (e.g., are non-genic or intergenic) and they are associated with an OR of at least 7 (Exon+ve, PML>4, NVE<2). For example, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregion does not overlap a known gene (e.g., is non-genic or intergenic) and/or non-overlapping, impact an exon, affect 2 or more PML cases but only 0 or 1 Normal subjects and are associated with an OR of at least 8, 9, 10, 11, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, or more. In some embodiments, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions are overlapping and/or non-overlapping, impact an exon, affect 2 or more PML cases but only 0 or 1 Normal subjects and are associated with an OR from about 7-100, 7-50, 7-40, 7-30, 7-20, 20-100, 20-50, 20-40, 20-30, 30-100, 30-50, 30-40, 40-100, 40-50, 50-100, or 7-11.

In some embodiments, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions are overlapping and/or non-overlapping, impact an exon, and they affect 1-5 PML cases but only 0 or 1 Normal subjects. This can enable identification of rarer CNVs in cases with PML. In some embodiments, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions are overlapping and/or non-overlapping, impact an exon, and they affect 1 PML case but only 0 or 1 Normal subjects, and are associated with an OR greater than 1, such as 1.47, or from 1-2.5. In some embodiments, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions are overlapping and/or non-overlapping, impact an exon, and they affect 2 PML cases but only 0 or 1 Normal subjects and are associated with an OR greater than 2.5, such as 2.95, or from 2.5-4. In some embodiments, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions are overlapping and/or non-overlapping, impact an exon, and they affect 3 PML cases but only 0 or 1 Normal subjects and are associated with an OR greater than 4, such as 4.44, or from 4-5.5. In some embodiments, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions are overlapping and/or non-overlapping, impact an exon, and they affect 4 PML cases but only 0 or 1 Normal subjects and are associated with an OR greater than 5.5, such as 5.92, or from 5.5-6.8.

In some embodiments, CNVs/CNV-subregions can be of interest if the OR associated with the sum of PML cases and the sum of NVE subjects affecting the same gene (including distinct CNVs/CNV-subregions) is at least 6. For example, a CNV/CNV-subregion can be of interest if the OR associated with the sum of PML cases and the sum of NVE subjects affecting the same gene (including distinct CNVs/CNV-subregions) is at least 7, 8, 9, 10, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, or more. In some embodiments, a CNVs/CNV-subregions can be of interest if the OR associated with the sum of PML cases and the sum of NVE subjects affecting the same gene (including distinct CNVs/CNV-subregions) is from about 6-100, 6-50, 6-40, 6-30, 6-20, 6-10, 6-9, 6-8, 6-7, 8-100, 8-50. 8-40, 8-30, 8-20, 8-10, 10-100, 10-50, 10-40, 10-30, 10-20, 20-100, 20-50, 20-40, 20-30, 30-100, 30-50, 30-40, 40-100, 40-50, 50-100, or 5-7.

In some embodiments, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions impact an intron and they affect 5 or more PML cases but only 0 or 1 Normal subjects and they are associated with an OR of at least 7 (Intron+ve, PML>4, Normals<2). For example, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions impact an intron and they affect 5 or more PML cases but only 0 or 1 Normal subjects and they are associated with an OR of at least 8, 9, 10, 11, 12, 14, 16, 18, 20, 25, 30, 35, 40, 45, 50, or more. In some embodiments, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions impact an intron and they affect 5 or more PML cases but only 0 or 1 Normal subjects and they are associated with an OR from about 7-100, 7-50, 7-40, 7-30, 7-20, 20-100, 20-50, 20-40, 20-30, 30-100, 30-50, 30-40, 40-100, 40-50, 50-100, or 7-11. CNVs/CNV-subregions impacting introns can be pathogenic (e.g., such variants can result in alternatively spliced mRNAs or loss of a microRNA binding site, which may deleteriously impact the resulting protein's structure or expression level).

In some embodiments, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions occur within intergenic regions and are associated with an OR of greater than 30 (High OR intergenic (OR>30)). For example, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions occur within intergenic regions and are associated with an OR of greater than 31, 32, 33, 34, 35, 40, 45, 50, 66, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more. In some embodiments, CNVs/CNV-subregions can be of interest if the CNVs/CNV-subregions impact occur within intergenic regions and are associated with an OR from about 30-100, 30-90, 30-80, 30-70, 30-60, 30-50, 30-40, 40-100, 40-90, 40-80, 40-70, 40-60, 40-50, 50-100, 50-90, 50-80, 50-70, 50-60, 60-100, 60-90, 60-80, 60-70, 70-100, 70-90, 70-80, 80-100, 80-90, or 90-100.

In some embodiments, a CNV/CNV-subregion can be of interest if the CNV/CNV-subregion overlaps a known gene, and is associated with an OR of at least 10. In some embodiments, a CNV/CNV-subregion can be of interest if the CNV/CNV-subregion overlaps a known gene, is associated with an OR of at least 6, and if the OR associated with the sum of PML cases and the sum of NVE subjects affecting the same gene (including distinct CNV-subregions) is at least 6.

Methods of Treatment

One embodiment of the present disclosure provides methods, pharmaceutical compositions, and kits for the treatment of a condition in animal subjects. The condition can be HIV/AIDS, cancer, or an autoimmune disease. In some embodiments, the condition can be PML. For example, the condition can be multiple sclerosis. In some embodiments, the methods comprise administering one or more immunosuppressive medications. In some embodiments, the pharmaceutical compositions and kits comprise one or more immunosuppressive medications. The one or more immunosuppressive medications can be adalimumab (e.g., HUMIRA), alemtuzumab (e.g., LEMTRADA), alemtuzumab (e.g., CAMPATH), azathioprine (e.g., IMURAN), belimumab (e.g., BENLYSTA), bevacizumab (e.g., AVASTIN), bortezomib (e.g., VELCADE), eculizumab (e.g., SOLIRIS), leflunomide, brentuximab vedotin (e.g., ADCETRIS), cetuximab (e.g., ERBITUX), cyclophosphamid, dimethyl fumarate (e.g., TECFIDERA), efalizumab (e.g., RAPTIVA), fingolimod (e.g., GILENYA), fludarabine (e.g., FLUDARA), fumaric acid, imatinib (e.g., GLEEVEC, GLIVEC), infliximab (e.g., REMICADE), methotrexate (e.g., TREXALL, RHEUMATREX), mycophenolate mofetil (e.g., CELLCEPT), natalizumab (e.g., TYSABRI), rituximab (e.g., RITUXAN), daclizumab (e.g., ZINBRYTA), vedolizumab (ENTYVIO), ruxolitinib (e.g., JAKAFI, JAKAVI), ocrelizumab (e.g., OCREVUS), or any combinations thereof. The term “animal subject” as used herein includes humans as well as other mammals. The term “treating” as used herein includes achieving a therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying viral infection (e.g., HIV), cancer, or autoimmune disease.

In some embodiments, a subject can be currently treated with an antiretroviral medication. In some embodiments, a subject can be previously treated with an antiretroviral medication. In some embodiments, a subject can be not yet treated with an antiretroviral medication. The antiretroviral medication can include but not limited to Nucleoside Reverse Transcriptase Inhibitors (NRTIs), Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), Protease Inhibitors (PIs), Fusion Inhibitors, Entry Inhibitors, Integrase Inhibitors, Pharmacokinetic Enhancers, and Combination HIV Medicines. In some cases, the Nucleoside Reverse Transcriptase Inhibitors can include but not limited to abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir disoproxil fumarate, and zidovudine. In some cases, the Non-Nucleoside Reverse Transcriptase Inhibitors can include but not limited to efavirenz, etravirine, nevirapine, and rilpivirine. In some cases, the Protease Inhibitors can include but not limited to atazanavir, darunavir, fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, and tipranavir. In some cases, the Fusion Inhibitors can include but not limited to enfuvirtide. In some cases, the Entry Inhibitors can include but not limited to maraviroc. In some cases, the Integrase Inhibitors can include but not limited to dolutegravir, elvitegravir, and raltegravir. In some cases, the Pharmacokinetic Enhancers can include but not limited to cobicistat. In some cases, the Combination HIV Medicines can include but not limited to abacavir and lamivudine, abacavir, dolutegravir, and lamivudine, abacavir, lamivudine, and zidovudine, atazanavir and cobicistat, darunavir and cobicistat, efavirenz, emtricitabine, and tenofovir disoproxil fumarate, elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate, elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate, emtricitabine, rilpivirine, and tenofovir alafenamide, emtricitabine, rilpivirine, and tenofovir disoproxil fumarate, emtricitabine and tenofovir alafenamide, emtricitabine and tenofovir disoproxil fumarate, lamivudine and zidovudine, lopinavir and ritonavir, and any combination of antiretroviral medications listed above.

In some embodiments, such as when a subject is identified as having at least one of the genetic variants described herein, an agent targeting the JC Virus can be administered to the subject. In some embodiments, a medication can be administered to a subject that prevents PML from developing, or it can reduce, lessen, shorten and/or otherwise ameliorate the progression of PML, or symptoms that develop. The pharmaceutical composition can modulate or target JC Virus. In some embodiments, a subject identified as having PML can be administered an agent that reduces a viral load in the subject. In some embodiments, an immunosuppressive agent can be administered prior to, or in conjunction with, an agent that reduces a viral load in the subject. In some embodiments, a subject identified as having a risk of developing PML can be administered an agent that prevents an increase in a viral load in the subject. In some embodiments, a subject identified as having a high risk of developing PML can be administered an agent that prevents an increase in a viral load in the subject. In some embodiments, an immunosuppressive agent can be administered prior to, or in conjunction with, an agent that prevents an increase in a viral load in the subject. The agent that reduces a viral load in the subject or that prevents an increase in a viral load in the subject can be, for example, an agent that targets JC Virus. Exemplary agents include antibodies, such as broadly neutralizing JCV antibodies. For example, an agent can be a broadly neutralizing human monoclonal JC polyomavirus VP-1 specific antibody (See, e.g., Jelcic et al., Science Translational Medicine, Vol. 7, Issue 306, pp. 306ra150 (2015) and Ray et al., Science Translational Medicine, Vol. 7, Issue 306, pp 306ra151 (2015)). Additional exemplary agents include antiretroviral agents, cidofovir, hexadecyloxypropyl-cidofovir (a lipid-ester derivative), cytarabine (e.g., cytosine arabinoside), agents that block the 5HT2a receptor (e.g., olanzapine, zisprasidone, mirtazapine, cyproheptadine, and risperidone), topoisomerase inhibitors (e.g., topotecan), and mefloquine.

In some embodiments, a pharmaceutical composition of the disclosure can be administered to a subject at risk of developing PML, or to a subject reporting one or more of the physiological symptoms of PML, even though a screening of the condition cannot have been made. In some embodiments, a pharmaceutical composition of the disclosure can be administered to a subject not identified as having a risk of developing PML, or to a subject not identified as having one or more of the physiological symptoms of PML, even though a screening of the condition cannot have been made.

The present disclosure also includes kits that can be used to treat a condition in animal subjects. These kits comprise one or more immunosuppressive medications and in some embodiments instructions teaching the use of the kit according to the various methods and approaches described herein. Such kits can also include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages (or risks and/or disadvantages) of the agent. Such information can be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials. Kits described herein can be provided, marketed and/or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like.

In some aspects a host cell can be used for testing or administering therapeutics. In some embodiments, a host cell can comprise a nucleic acid comprising expression control sequences operably-linked to a coding region. The host cell can be natural or non-natural. The non-natural host used in aspects of the method can be any cell capable of expressing a nucleic acid of the disclosure including, bacterial cells, fungal cells, insect cells, mammalian cells and plant cells. In some aspects the natural host is a mammalian tissue cell and the non-natural host is a different mammalian tissue cell. Other aspects of the method include a natural host that is a first cell normally residing in a first mammalian species and the non-natural host is a second cell normally residing in a second mammalian species. In another alternative aspect, the method uses a first cell and the second cell that are from the same tissue type. In those aspects of the method where the coding region encodes a mammalian polypeptide, the mammalian polypeptide may be a hormone. In other aspects the coding region may encode a neuropeptide, an antibody, an antimetabolite, or a polypeptide or nucleotide therapeutic.

Expression control sequences can be those nucleotide sequences, both 5′ and 3′ to a coding region, that are required for the transcription and translation of the coding region in a host organism. Regulatory sequences include a promoter, ribosome binding site, optional inducible elements and sequence elements required for efficient 3′ processing, including polyadenylation. When the structural gene has been isolated from genomic DNA, the regulatory sequences also include those intronic sequences required for splicing of the introns as part of mRNA formation in the target host.

Formulations, Routes of Administration, and Effective Doses

Yet another aspect of the present disclosure relates to formulations, routes of administration and effective doses for pharmaceutical compositions comprising an agent or combination of agents of the instant disclosure. Such pharmaceutical compositions can be used to treat a condition (e.g., multiple sclerosis) as described above.

Compounds of the disclosure can be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, transdermal patch, pulmonary, vaginal, suppository, or parenteral (including intramuscular, intraarterial, intrathecal, intradermal, intraperitoneal, subcutaneous and intravenous) administration or in a form suitable for administration by aerosolization, inhalation or insufflation. General information on drug delivery systems can be found in Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (Lippencott Williams & Wilkins, Baltimore Md. (1999).

In various embodiments, the pharmaceutical composition includes carriers and excipients (including but not limited to buffers, carbohydrates, mannitol, polypeptides, amino acids, antioxidants, bacteriostats, chelating agents, suspending agents, thickening agents and/or preservatives), water, oils including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like, saline solutions, aqueous dextrose and glycerol solutions, flavoring agents, coloring agents, detackifiers and other acceptable additives, adjuvants, or binders, other pharmaceutically acceptable auxiliary substances to approximate physiological conditions, such as pH buffering agents, tonicity adjusting agents, emulsifying agents, wetting agents and the like. Examples of excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. In some embodiments, the pharmaceutical preparation is substantially free of preservatives. In other embodiments, the pharmaceutical preparation can contain at least one preservative. General methodology on pharmaceutical dosage forms is found in Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (Lippencott, Williams, & Wilkins, Baltimore Md. (1999)). It can be recognized that, while any suitable carrier known to those of ordinary skill in the art can be employed to administer the compositions of this disclosure, the type of carrier can vary depending on the mode of administration.

Compounds can also be encapsulated within liposomes using well-known technology. Biodegradable microspheres can also be employed as carriers for the pharmaceutical compositions of this disclosure. Suitable biodegradable microspheres are disclosed, for example, in U.S. Pat. Nos. 4,897,268, 5,075,109, 5,928,647, 5,811,128, 5,820,883, 5,853,763, 5,814,344 and 5,942,252.

The compound can be administered in liposomes or microspheres (or microparticles). Methods for preparing liposomes and microspheres for administration to a subject are well known to those of skill in the art. U.S. Pat. No. 4,789,734, the contents of which are hereby incorporated by reference, describes methods for encapsulating biological materials in liposomes. Essentially, the material is dissolved in an aqueous solution, the appropriate phospholipids and lipids added, and along with surfactants if required, and the material dialyzed or sonicated, as necessary. A review of known methods is provided by G. Gregoriadis, Chapter 14, “Liposomes,” Drug Carriers in Biology and Medicine, pp. 2.sup.87-341 (Academic Press, 1979).

Microspheres formed of polymers or polypeptides are well known to those skilled in the art, and can be tailored for passage through the gastrointestinal tract directly into the blood stream. Alternatively, the compound can be incorporated and the microspheres, or composite of microspheres, implanted for slow release over a period of time ranging from days to months. See, for example, U.S. Pat. Nos. 4,906,474, 4,925,673 and 3,625,214, and Jein, TIPS 19:155-157 (1998), the contents of which are hereby incorporated by reference.

The concentration of drug can be adjusted, the pH of the solution buffered and the isotonicity adjusted to be compatible with intravenous injection, as is well known in the art.

The compounds of the disclosure can be formulated as a sterile solution or suspension, in suitable vehicles, well known in the art. The pharmaceutical compositions can be sterilized by conventional, well-known sterilization techniques, or can be sterile filtered. The resulting aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile solution prior to administration. Suitable formulations and additional carriers are described in Remington “The Science and Practice of Pharmacy” (20th Ed., Lippincott Williams & Wilkins, Baltimore Md.), the teachings of which are incorporated by reference in their entirety herein.

The agents or their pharmaceutically acceptable salts can be provided alone or in combination with one or more other agents or with one or more other forms. For example, a formulation can comprise one or more agents in particular proportions, depending on the relative potencies of each agent and the intended indication. For example, in compositions for targeting two different host targets, and where potencies are similar, about a 1:1 ratio of agents can be used. The two forms can be formulated together, in the same dosage unit e.g., in one cream, suppository, tablet, capsule, aerosol spray, or packet of powder to be dissolved in a beverage; or each form can be formulated in a separate unit, e.g., two creams, two suppositories, two tablets, two capsules, a tablet and a liquid for dissolving the tablet, two aerosol sprays, or a packet of powder and a liquid for dissolving the powder, etc.

The term “pharmaceutically acceptable salt” means those salts which retain the biological effectiveness and properties of the agents used in the present disclosure, and which are not biologically or otherwise undesirable.

Typical salts are those of the inorganic ions, such as, for example, sodium, potassium, calcium, magnesium ions, and the like. Such salts include salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, p toluenesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, mandelic acid, malic acid, citric acid, tartaric acid or maleic acid. In addition, if the agent(s) contain a carboxyl group or other acidic group, it can be converted into a pharmaceutically acceptable addition salt with inorganic or organic bases. Examples of suitable bases include sodium hydroxide, potassium hydroxide, ammonia, cyclohexylamine, dicyclohexyl-amine, ethanolamine, diethanolamine, triethanolamine, and the like.

A pharmaceutically acceptable ester or amide refers to those which retain biological effectiveness and properties of the agents used in the present disclosure, and which are not biologically or otherwise undesirable. Typical esters include ethyl, methyl, isobutyl, ethylene glycol, and the like. Typical amides include unsubstituted amides, alkyl amides, dialkyl amides, and the like.

In some embodiments, an agent can be administered in combination with one or more other compounds, forms, and/or agents, e.g., as described above. Pharmaceutical compositions with one or more other active agents can be formulated to comprise certain molar ratios. For example, molar ratios of about 99:1 to about 1:99 of a first active agent to the other active agent can be used. In some subset of the embodiments, the range of molar ratios of a first active agent: other active agents are selected from about 80:20 to about 20:80; about 75:25 to about 25:75, about 70:30 to about 30:70, about 66:33 to about 33:66, about 60:40 to about 40:60; about 50:50; and about 90:10 to about 10:90. The molar ratio of a first active: other active agents can be about 1:9, and in some embodiments can be about 1:1. The two agents, forms and/or compounds can be formulated together, in the same dosage unit e.g., in one cream, suppository, tablet, capsule, or packet of powder to be dissolved in a beverage; or each agent, form, and/or compound can be formulated in separate units, e.g., two creams, suppositories, tablets, two capsules, a tablet and a liquid for dissolving the tablet, an aerosol spray a packet of powder and a liquid for dissolving the powder, etc.

If necessary or desirable, the agents and/or combinations of agents can be administered with still other agents. The choice of agents that can be co-administered with the agents and/or combinations of agents of the instant disclosure can depend, at least in part, on the condition being treated. Agents of particular use in the formulations of the present disclosure include, for example, any agent having a therapeutic effect for a viral infection, including, e.g., drugs used to treat inflammatory conditions. For example, in treatments for influenza, in some embodiments formulations of the instant disclosure can additionally contain one or more conventional anti-inflammatory drugs, such as an NSAID, e.g., ibuprofen, naproxen, acetaminophen, ketoprofen, or aspirin. In some alternative embodiments for the treatment of influenza formulations of the instant disclosure can additionally contain one or more conventional influenza antiviral agents, such as amantadine, rimantadine, zanamivir, and oseltamivir. In treatments for retroviral infections, such as HIV, formulations of the instant disclosure can additionally contain one or more conventional antiviral drug, such as protease inhibitors (lopinavir/ritonavir {e.g., KALETRA}, indinavir {e.g., CRIXIVAN}, ritonavir {e.g., NORVIR}, nelfinavir {e.g., VIRACEPT}, saquinavir hard gel capsules {e.g., INVIRASE}, atazanavir {e.g., REYATAZ}, amprenavir {e.g., AGENERASE}, fosamprenavir {e.g., TELZIR}, tipranavir{e.g., APTIVUS}), reverse transcriptase inhibitors, including non-nucleoside and nucleoside/nucleotide inhibitors (AZT {zidovudine, e.g., Retrovir}, ddI {didanosine, e.g., VIDEX}, 3TC {lamivudine, e.g., EPIVIR}, d4T {stavudine, e.g., ZERIT}, abacavir {e.g., ZIAGEN}, FTC {emtricitabine, e.g., EMTRIVA}, tenofovir {e.g., VIREAD}, efavirenz {e.g., SUSTIVA} and nevirapine {e.g., VIRAMUNE}), fusion inhibitors T20 {enfuvirtide, e.g., FUZEON}, integrase inhibitors (Raltegravir, e.g., ISENTRESS, MK-0518; and elvitegravir, e.g., VITEKTA, GS-9137), and maturation inhibitors (bevirimat {PA-457}). As another example, formulations can additionally contain one or more supplements, such as vitamin C, E or other anti-oxidants.

The agent(s) (or pharmaceutically acceptable salts, esters or amides thereof) can be administered per se or in the form of a pharmaceutical composition wherein the active agent(s) is in an admixture or mixture with one or more pharmaceutically acceptable carriers. A pharmaceutical composition, as used herein, can be any composition prepared for administration to a subject. Pharmaceutical compositions for use in accordance with the present disclosure can be formulated in conventional manner using one or more physiologically acceptable carriers, comprising excipients, diluents, and/or auxiliaries, e.g., which facilitate processing of the active agents into preparations that can be administered. Proper formulation can depend at least in part upon the route of administration chosen. The agent(s) useful in the present disclosure, or pharmaceutically acceptable salts, esters, or amides thereof, can be delivered to a subject using a number of routes or modes of administration, including oral, buccal, topical, rectal, transdermal, transmucosal, subcutaneous, intravenous, and intramuscular applications, as well as by inhalation.

For oral administration, the agents can be formulated readily by combining the active agent(s) with pharmaceutically acceptable carriers well known in the art. Such carriers enable the agents of the disclosure to be formulated as tablets, including chewable tablets, pills, dragees, capsules, lozenges, hard candy, liquids, gels, syrups, slurries, powders, suspensions, elixirs, wafers, and the like, for oral ingestion by a subject to be treated. Such formulations can comprise pharmaceutically acceptable carriers including solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. A solid carrier can be one or more substances which can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about one (1) to about seventy (70) percent of the active compound. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. Generally, the agents of the disclosure can be included at concentration levels ranging from about 0.5%, about 5%, about 10%, about 20%, or about 30% to about 50%, about 60%, about 70%, about 80% or about 90% by weight of the total composition of oral dosage forms, in an amount sufficient to provide a desired unit of dosage.

Aqueous suspensions for oral use can contain agent(s) of this disclosure with pharmaceutically acceptable excipients, such as a suspending agent (e.g., methyl cellulose), a wetting agent (e.g., lecithin, lysolecithin and/or a long-chain fatty alcohol), as well as coloring agents, preservatives, flavoring agents, and the like.

In some embodiments, oils or non-aqueous solvents can be used to bring the agents into solution, due to, for example, the presence of large lipophilic moieties. Alternatively, emulsions, suspensions, or other preparations, for example, liposomal preparations, can be used. With respect to liposomal preparations, any known methods for preparing liposomes for treatment of a condition can be used. See, for example, Bangham et al., J. Mol. Biol. 23: 238-252 (1965) and Szoka et al., Proc. Natl Acad. Sci. USA 75: 4194-4198 (1978), incorporated herein by reference. Ligands can also be attached to the liposomes to direct these compositions to particular sites of action. Agents of this disclosure can also be integrated into foodstuffs, e.g., cream cheese, butter, salad dressing, or ice cream to facilitate solubilization, administration, and/or compliance in certain subject populations.

Pharmaceutical preparations for oral use can be obtained as a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; flavoring elements, cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone (PVP). If desired, disintegrating agents can be added, such as the cross linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. The agents can also be formulated as a sustained release preparation.

Dragee cores can be provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.

Pharmaceutical preparations that can be used orally include push fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active agents can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration should be in dosages suitable for administration.

Other forms suitable for oral administration include liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations. Emulsions can be prepared in solutions, for example, in aqueous propylene glycol solutions or can contain emulsifying agents, for example, such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents. Suitable fillers or carriers with which the compositions can be administered include agar, alcohol, fats, lactose, starch, cellulose derivatives, polysaccharides, polyvinylpyrrolidone, silica, sterile saline and the like, or mixtures thereof used in suitable amounts. Solid form preparations include solutions, suspensions, and emulsions, and can contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

A syrup or suspension can be made by adding the active compound to a concentrated, aqueous solution of a sugar, e.g., sucrose, to which can also be added any accessory ingredients. Such accessory ingredients can include flavoring, an agent to retard crystallization of the sugar or an agent to increase the solubility of any other ingredient, e.g., as a polyhydric alcohol, for example, glycerol or sorbitol.

When formulating compounds of the disclosure for oral administration, it can be desirable to utilize gastroretentive formulations to enhance absorption from the gastrointestinal (GI) tract. A formulation which is retained in the stomach for several hours can release compounds of the disclosure slowly and provide a sustained release that can be preferred in some embodiments of the disclosure. Disclosure of such gastro-retentive formulations are found in Klausner E. A., et al., Pharm. Res. 20, 1466-73 (2003); Hoffman, A. et al., Int. J. Pharm. 11, 141-53 (2004), Streubel, A., et al. Expert Opin. Drug Deliver. 3, 217-3, and Chavanpatil, M. D. et al., Int. J. Pharm. (2006). Expandable, floating and bioadhesive techniques can be utilized to maximize absorption of the compounds of the disclosure.

The compounds of the disclosure can be formulated for parenteral administration (e.g., by injection, for example, bolus injection or continuous infusion) and can be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example, solutions in aqueous polyethylene glycol.

For injectable formulations, the vehicle can be chosen from those known in art to be suitable, including aqueous solutions or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. The formulation can also comprise polymer compositions which are biocompatible, biodegradable, such as poly(lactic-co-glycolic)acid. These materials can be made into micro or nanospheres, loaded with drug and further coated or derivatized to provide superior sustained release performance. Vehicles suitable for periocular or intraocular injection include, for example, suspensions of therapeutic agent in injection grade water, liposomes and vehicles suitable for lipophilic substances. Other vehicles for periocular or intraocular injection are well known in the art.

In some embodiments, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where necessary, the composition can also include a solubilizing agent and a local anesthetic such as lidocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

When administration is by injection, the active compound can be formulated in aqueous solutions, specifically in physiologically compatible buffers such as Hanks solution, Ringer's solution, or physiological saline buffer. The solution can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active compound can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. In some embodiments, the pharmaceutical composition does not comprise an adjuvant or any other substance added to enhance the immune response stimulated by the peptide. In some embodiments, the pharmaceutical composition comprises a substance that inhibits an immune response to the peptide. Methods of formulation are known in the art, for example, as disclosed in Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Co., Easton P.

In addition to the formulations described previously, the agents can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation or transcutaneous delivery (for example, subcutaneously or intramuscularly), intramuscular injection or use of a transdermal patch. Thus, for example, the agents can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

In some embodiments, pharmaceutical compositions comprising one or more agents of the present disclosure exert local and regional effects when administered topically or injected at or near particular sites of infection. Direct topical application, e.g., of a viscous liquid, solution, suspension, dimethylsulfoxide (DMSO)-based solutions, liposomal formulations, gel, jelly, cream, lotion, ointment, suppository, foam, or aerosol spray, can be used for local administration, to produce for example, local and/or regional effects. Pharmaceutically appropriate vehicles for such formulation include, for example, lower aliphatic alcohols, polyglycols (e.g., glycerol or polyethylene glycol), esters of fatty acids, oils, fats, silicones, and the like. Such preparations can also include preservatives (e.g., p-hydroxybenzoic acid esters) and/or antioxidants (e.g., ascorbic acid and tocopherol). See also Dermatological Formulations: Percutaneous absorption, Barry (Ed.), Marcel Dekker Incl, 1983.

Pharmaceutical compositions of the present disclosure can contain a cosmetically or dermatologically acceptable carrier. Such carriers are compatible with skin, nails, mucous membranes, tissues and/or hair, and can include any conventionally used cosmetic or dermatological carrier meeting these requirements. Such carriers can be readily selected by one of ordinary skill in the art. In formulating skin ointments, an agent or combination of agents of the instant disclosure can be formulated in an oleaginous hydrocarbon base, an anhydrous absorption base, a water-in-oil absorption base, an oil-in-water water-removable base and/or a water-soluble base. Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

Ointments and creams can, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions can be formulated with an aqueous or oily base and can in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches can be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

Lubricants which can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof. A lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.

The compositions according to the present disclosure can be in any form suitable for topical application, including aqueous, aqueous-alcoholic or oily solutions, lotion or serum dispersions, aqueous, anhydrous or oily gels, emulsions obtained by dispersion of a fatty phase in an aqueous phase (O/W or oil in water) or, conversely, (W/O or water in oil), microemulsions or alternatively microcapsules, microparticles or lipid vesicle dispersions of ionic and/or nonionic type. These compositions can be prepared according to conventional methods. Other than the agents of the disclosure, the amounts of the various constituents of the compositions according to the disclosure are those conventionally used in the art. These compositions in particular constitute protection, treatment or care creams, milks, lotions, gels or foams for the face, for the hands, for the body and/or for the mucous membranes, or for cleansing the skin. The compositions can also consist of solid preparations constituting soaps or cleansing bars.

Compositions of the present disclosure can also contain adjuvants common to the cosmetic and dermatological fields, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active agents, preserving agents, antioxidants, solvents, fragrances, fillers, sunscreens, odor-absorbers and dyestuffs. The amounts of these various adjuvants are those conventionally used in the fields considered and, for example, are from about 0.01% to about 20% of the total weight of the composition. Depending on their nature, these adjuvants can be introduced into the fatty phase, into the aqueous phase and/or into the lipid vesicles.

In some embodiments, ocular viral infections can be effectively treated with ophthalmic solutions, suspensions, ointments or inserts comprising an agent or combination of agents of the present disclosure. Eye drops can be prepared by dissolving the active ingredient in a sterile aqueous solution such as physiological saline, buffering solution, etc., or by combining powder compositions to be dissolved before use. Other vehicles can be chosen, as is known in the art, including but not limited to: balance salt solution, saline solution, water soluble polyethers such as polyethyene glycol, polyvinyls, such as polyvinyl alcohol and povidone, cellulose derivatives such as methylcellulose and hydroxypropyl methylcellulose, petroleum derivatives such as mineral oil and white petrolatum, animal fats such as lanolin, polymers of acrylic acid such as carboxypolymethylene gel, vegetable fats such as peanut oil and polysaccharides such as dextrans, and glycosaminoglycans such as sodium hyaluronate. If desired, additives ordinarily used in the eye drops can be added. Such additives include isotonizing agents (e.g., sodium chloride, etc.), buffer agent (e.g., boric acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate, etc.), preservatives (e.g., benzalkonium chloride, benzethonium chloride, chlorobutanol, etc.), thickeners (e.g., saccharide such as lactose, mannitol, maltose, etc.; e.g., hyaluronic acid or its salt such as sodium hyaluronate, potassium hyaluronate, etc.; e.g., mucopolysaccharide such as chondroitin sulfate, etc.; e.g., sodium polyacrylate, carboxyvinyl polymer, crosslinked polyacrylate, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose or other agents known to those skilled in the art).

The solubility of the components of the present compositions can be enhanced by a surfactant or other appropriate co-solvent in the composition. Such cosolvents include polysorbate 20, 60, and 80, Pluronic F68, F-84 and P-103, cyclodextrin, or other agents known to those skilled in the art. Such co-solvents can be employed at a level of from about 0.01% to 2% by weight.

The compositions of the disclosure can be packaged in multidose form. Preservatives can be preferred to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, Onamer M, or other agents known to those skilled in the art. In the prior art ophthalmic products, such preservatives can be employed at a level of from 0.004% to 0.02%. In the compositions of the present application the preservative, preferably benzalkonium chloride, can be employed at a level of from 0.001% to less than 0.01%, e.g., from 0.001% to 0.008%, preferably about 0.005% by weight. It has been found that a concentration of benzalkonium chloride of 0.005% can be sufficient to preserve the compositions of the present disclosure from microbial attack.

In some embodiments, the agents of the present disclosure are delivered in soluble rather than suspension form, which allows for more rapid and quantitative absorption to the sites of action. In general, formulations such as jellies, creams, lotions, suppositories and ointments can provide an area with more extended exposure to the agents of the present disclosure, while formulations in solution, e.g., sprays, provide more immediate, short-term exposure.

In some embodiments relating to topical/local application, the pharmaceutical compositions can include one or more penetration enhancers. For example, the formulations can comprise suitable solid or gel phase carriers or excipients that increase penetration or help delivery of agents or combinations of agents of the disclosure across a permeability barrier, e.g., the skin. Many of these penetration-enhancing compounds are known in the art of topical formulation, and include, e.g., water, alcohols (e.g., terpenes like methanol, ethanol, 2-propanol), sulfoxides (e.g., dimethyl sulfoxide, decylmethyl sulfoxide, tetradecylmethyl sulfoxide), pyrrolidones (e.g., 2-pyrrolidone, N-methyl-2-pyrrolidone, N-(2-hydroxyethyl)pyrrolidone), laurocapram, acetone, dimethylacetamide, dimethylformamide, tetrahydrofurfuryl alcohol, L-a-amino acids, anionic, cationic, amphoteric or nonionic surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), fatty acids, fatty alcohols (e.g., oleic acid), amines, amides, clofibric acid amides, hexamethylene lauramide, proteolytic enzymes, a-bisabolol, d-limonene, urea and N,N-diethyl-m-toluamide, and the like. Additional examples include humectants (e.g., urea), glycols (e.g., propylene glycol and polyethylene glycol), glycerol monolaurate, alkanes, alkanols, ORGELASE, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and/or other polymers. In some embodiments, the pharmaceutical compositions can include one or more such penetration enhancers.

In some embodiments, the pharmaceutical compositions for local/topical application can include one or more antimicrobial preservatives such as quaternary ammonium compounds, organic mercurials, p-hydroxy benzoates, aromatic alcohols, chlorobutanol, and the like.

In some embodiments, the pharmaceutical compositions can be orally- or rectally delivered solutions, suspensions, ointments, enemas and/or suppositories comprising an agent or combination of agents of the present disclosure.

In some embodiments, the pharmaceutical compositions can be aerosol solutions, suspensions or dry powders comprising an agent or combination of agents of the present disclosure. The aerosol can be administered through the respiratory system or nasal passages. For example, one skilled in the art can recognize that a composition of the present disclosure can be suspended or dissolved in an appropriate carrier, e.g., a pharmaceutically acceptable propellant, and administered directly into the lungs using a nasal spray or inhalant. For example, an aerosol formulation comprising an agent can be dissolved, suspended or emulsified in a propellant or a mixture of solvent and propellant, e.g., for administration as a nasal spray or inhalant. Aerosol formulations can contain any acceptable propellant under pressure, such as a cosmetically or dermatologically or pharmaceutically acceptable propellant, as conventionally used in the art.

An aerosol formulation for nasal administration is generally an aqueous solution designed to be administered to the nasal passages in drops or sprays. Nasal solutions can be similar to nasal secretions in that they are generally isotonic and slightly buffered to maintain a pH of about 5.5 to about 6.5, although pH values outside of this range can additionally be used. Antimicrobial agents or preservatives can also be included in the formulation.

An aerosol formulation for inhalations and inhalants can be designed so that the agent or combination of agents of the present disclosure is carried into the respiratory tree of the subject when administered by the nasal or oral respiratory route. Inhalation solutions can be administered, for example, by a nebulizer. Inhalations or insufflations, comprising finely powdered or liquid drugs, can be delivered to the respiratory system as a pharmaceutical aerosol of a solution or suspension of the agent or combination of agents in a propellant, e.g., to aid in disbursement. Propellants can be liquefied gases, including halocarbons, for example, fluorocarbons such as fluorinated chlorinated hydrocarbons, hydrochlorofluorocarbons, and hydrochlorocarbons, as well as hydrocarbons and hydrocarbon ethers.

Halocarbon propellants useful in the present disclosure include fluorocarbon propellants in which all hydrogens are replaced with fluorine, chlorofluorocarbon propellants in which all hydrogens are replaced with chlorine and at least one fluorine, hydrogen-containing fluorocarbon propellants, and hydrogen-containing chlorofluorocarbon propellants. Halocarbon propellants are described in Johnson, U.S. Pat. No. 5,376,359; Byron et al., U.S. Pat. No. 5,190,029; and Purewal et al., U.S. Pat. No. 5,776,434. Hydrocarbon propellants useful in the disclosure include, for example, propane, isobutane, n-butane, pentane, isopentane and neopentane. A blend of hydrocarbons can also be used as a propellant. Ether propellants include, for example, dimethyl ether as well as the ethers. An aerosol formulation of the disclosure can also comprise more than one propellant. For example, the aerosol formulation can comprise more than one propellant from the same class, such as two or more fluorocarbons; or more than one, more than two, more than three propellants from different classes, such as a fluorohydrocarbon and a hydrocarbon. Pharmaceutical compositions of the present disclosure can also be dispensed with a compressed gas, e.g., an inert gas such as carbon dioxide, nitrous oxide or nitrogen.

Aerosol formulations can also include other components, for example, ethanol, isopropanol, propylene glycol, as well as surfactants or other components such as oils and detergents. These components can serve to stabilize the formulation and/or lubricate valve components.

The aerosol formulation can be packaged under pressure and can be formulated as an aerosol using solutions, suspensions, emulsions, powders and semisolid preparations. For example, a solution aerosol formulation can comprise a solution of an agent of the disclosure in (substantially) pure propellant or as a mixture of propellant and solvent. The solvent can be used to dissolve the agent and/or retard the evaporation of the propellant. Solvents useful in the disclosure include, for example, water, ethanol and glycols. Any combination of suitable solvents can be use, optionally combined with preservatives, antioxidants, and/or other aerosol components.

An aerosol formulation can also be a dispersion or suspension. A suspension aerosol formulation can comprise a suspension of an agent or combination of agents of the instant disclosure. Dispersing agents useful in the disclosure include, for example, sorbitan trioleate, oleyl alcohol, oleic acid, lecithin and corn oil. A suspension aerosol formulation can also include lubricants, preservatives, antioxidant, and/or other aerosol components.

An aerosol formulation can similarly be formulated as an emulsion. An emulsion aerosol formulation can include, for example, an alcohol such as ethanol, a surfactant, water and a propellant, as well as an agent or combination of agents of the disclosure. The surfactant used can be nonionic, anionic or cationic. One example of an emulsion aerosol formulation comprises, for example, ethanol, surfactant, water and propellant. Another example of an emulsion aerosol formulation comprises, for example, vegetable oil, glyceryl monostearate and propane.

The compounds of the disclosure can be formulated for administration as suppositories. A low melting wax, such as a mixture of triglycerides, fatty acid glycerides, Witepsol S55 (trademark of Dynamite Nobel Chemical, Germany), or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify.

The compounds of the disclosure can be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

It is envisioned additionally, that the compounds of the disclosure can be attached releasably to biocompatible polymers for use in sustained release formulations on, in or attached to inserts for topical, intraocular, periocular, or systemic administration. The controlled release from a biocompatible polymer can be utilized with a water soluble polymer to form an instillable formulation, as well. The controlled release from a biocompatible polymer, such as for example, PLGA microspheres or nanospheres, can be utilized in a formulation suitable for intra ocular implantation or injection for sustained release administration, as well any suitable biodegradable and biocompatible polymer can be used.

In one aspect of the disclosure, the subject's carrier status of any of the genetic variation risk variants described herein, or genetic variants identified via other analysis methods within the genes or regulatory loci that are identified by the CNVs or SNVs described herein, can be used to help determine whether a particular treatment modality, such as any one of the above, or a combination thereof, should be administered. Whether a treatment option such as any of the above mentioned treatment options is administered can be determined based on the presence or absence of a particular genetic variation risk variant in the individual, or by monitoring expression of genes that are associated with the variants of the present disclosure. Expression levels and/or mRNA levels can thus be determined before and during treatment to monitor its effectiveness. Alternatively, or concomitantly, the status with respect to a genetic variation, and or genotype and/or haplotype status of at least one risk variant for PML presented herein can be determined before and during treatment to monitor its effectiveness. It can also be appreciated by those skilled in the art that aberrant expression levels of a gene impacted by a CNV or other mutations found as a consequence of targeted sequencing of the CNV-identified gene can be assayed or diagnostically tested for by measuring the polypeptide expression level of said aberrantly expressed gene. In another embodiment, aberrant expression levels of a gene may result from a CNV impacting a DNA sequence (e.g., transcription factor binding site) that regulates a gene whose aberrant expression level is involved in or causes PML, or other mutations found as a consequence of targeted sequencing of the CNV-identified gene regulatory sequence, can be assayed or diagnostically tested for by measuring the polypeptide expression level of the gene involved in or causative of PML. In some embodiments, a specific CNV mutation within a gene, or other specific mutations found upon targeted sequencing of a CNV-identified gene found to be involved in or causative of PML, may cause an aberrant structural change in the expressed polypeptide that results from said gene mutations and the altered polypeptide structure(s) can be assayed via various methods know to those skilled in the art.

Alternatively, biological networks or metabolic pathways related to the genes within, or associated with, the genetic variations described herein can be monitored by determining mRNA and/or polypeptide levels. This can be done for example, by monitoring expression levels of polypeptides for several genes belonging to the network and/or pathway in nucleic acid samples taken before and during treatment. Alternatively, metabolites belonging to the biological network or metabolic pathway can be determined before and during treatment. Effectiveness of the treatment is determined by comparing observed changes in expression levels/metabolite levels during treatment to corresponding data from healthy subjects.

In some embodiments, the genetic variations described herein and/or those subsequently found (e.g., via other genetic analysis methods such as sequencing) via targeted analysis of those genes initially identified by the genetic variations described herein, can be used to prevent adverse effects associated with a therapeutic agent, such as during clinical trials. For example, individuals who are carriers of at least one at-risk genetic variation can be more likely to respond negatively to a therapeutic agent, such as an immunosuppressive agent. For example, carriers of certain genetic variants may be more likely to show an adverse response to the therapeutic agent. In some embodiments, one or more of the genetic variations employed during clinical trials for a given therapeutic agent can be used in a companion diagnostic test that is administered to the patient prior to administration of the therapeutic agent to determine if the patient is likely to have a favorable or an adverse response to the therapeutic agent.

The genetic variations described herein can be used for determining whether a subject is administered a pharmaceutical agent, such as an immunosuppressive drug. Certain combinations of variants, including those described herein, but also combinations with other risk variants for PML, can be suitable for one selection of treatment options, while other variant combinations can be suitable for selection of other treatment options. Such combinations of variants can include one variant, two variants, three variants, or four or more variants, as needed to determine with clinically reliable accuracy the selection of treatment module. In another embodiment, information from testing for the genetic variations described herein, or other rare genetic variations in or near the genes described herein, may be combined with information from other types of testing (e.g., a JCV antibody test, CD62L test, or CSF IgM oligoclonal bands test) for selection of treatment options.

Kits

Kits useful in the methods of the disclosure comprise components useful in any of the methods described herein, including for example, primers for nucleic acid amplification, hybridization probes for detecting genetic variation, or other marker detection, restriction enzymes, nucleic acid probes, optionally labeled with suitable labels, allele-specific oligonucleotides, antibodies that bind to an altered polypeptide encoded by a nucleic acid of the disclosure as described herein or to a wild type polypeptide encoded by a nucleic acid of the disclosure as described herein, means for amplification of genetic variations or fragments thereof, means for analyzing the nucleic acid sequence of nucleic acids comprising genetic variations as described herein, means for analyzing the amino acid sequence of a polypeptide encoded by a genetic variation, or a nucleic acid associated with a genetic variation, etc. The kits can for example, include necessary buffers, nucleic acid primers for amplifying nucleic acids, and reagents for allele-specific detection of the fragments amplified using such primers and necessary enzymes (e.g., DNA polymerase). Additionally, kits can provide reagents for assays to be used in combination with the methods of the present disclosure, for example, reagents for use with other screening assays for PML.

In some embodiments, the disclosure pertains to a kit for assaying a nucleic acid sample from a subject to detect the presence of a genetic variation, wherein the kit comprises reagents necessary for selectively detecting at least one particular genetic variation in the genome of the individual. In some embodiments, the disclosure pertains to a kit for assaying a nucleic acid sample from a subject to detect the presence of at least one particular allele of at least one polymorphism associated with a genetic variation in the genome of the subject. In some embodiments, the reagents comprise at least one contiguous oligonucleotide that hybridizes to a fragment of the genome of the individual comprising at least genetic variation. In some embodiments, the reagents comprise at least one pair of oligonucleotides that hybridize to opposite strands of a genomic segment obtained from a subject, wherein each oligonucleotide primer pair is designed to selectively amplify a fragment of the genome of the individual that includes at least one genetic variation, or a fragment of a genetic variation. Such oligonucleotides or nucleic acids can be designed using the methods described herein. In some embodiments, the kit comprises one or more labeled nucleic acids capable of allele-specific detection of one or more specific polymorphic markers or haplotypes with a genetic variation, and reagents for detection of the label. In some embodiments, a kit for detecting SNP markers can comprise a detection oligonucleotide probe, that hybridizes to a segment of template DNA containing a SNP polymorphism to be detected, an enhancer oligonucleotide probe, detection probe, primer and/or an endonuclease, for example, as described by Kutyavin et al., (Nucleic Acid Res. 34:e128 (2006)). In other embodiments, the kit can contain reagents for detecting SNVs and/or CNVs.

In some embodiments, the DNA template is amplified by any means of the present disclosure, prior to assessment for the presence of specific genetic variations as described herein Standard methods well known to the skilled person for performing these methods can be utilized, and are within scope of the disclosure. In one such embodiment, reagents for performing these methods can be included in the reagent kit.

In a further aspect of the present disclosure, a pharmaceutical pack (kit) is provided, the pack comprising a therapeutic agent and a set of instructions for administration of the therapeutic agent to humans screened for one or more variants of the present disclosure, as disclosed herein. The therapeutic agent can be a small molecule drug, an antibody, a peptide, an antisense or RNAi molecule, or other therapeutic molecules as described herein. In some embodiments, an individual identified as a non-carrier of at least one variant of the present disclosure is instructed to take the therapeutic agent. In one such embodiment, an individual identified as a non-carrier of at least one variant of the present disclosure is instructed to take a prescribed dose of the therapeutic agent. In some embodiments, an individual identified as a carrier of at least one variant of the present disclosure is instructed not to take the therapeutic agent. In some embodiments, an individual identified as a carrier of at least one variant of the present disclosure is instructed not to take a prescribed dose of the therapeutic agent. In some embodiments, an individual identified as a carrier of at least one variant of the present disclosure is instructed to take an agent that targets the JC Virus. For example, an individual identified as a carrier of at least one variant of the present disclosure can be instructed to take an agent that targets the JC Virus prior to or in conjunction with, taking an immunosuppressive agent.

Also provided herein are articles of manufacture, comprising a probe that hybridizes with a region of human chromosome as described herein and can be used to detect a polymorphism described herein. For example, any of the probes for detecting polymorphisms or genetic variations described herein can be combined with packaging material to generate articles of manufacture or kits. The kit can include one or more other elements including: instructions for use; and other reagents such as a label or an agent useful for attaching a label to the probe. Instructions for use can include instructions for screening applications of the probe for making a diagnosis, prognosis, or theranosis to PML in a method described herein. Other instructions can include instructions for attaching a label to the probe, instructions for performing in situ analysis with the probe, and/or instructions for obtaining a nucleic acid sample to be analyzed from a subject. In some cases, the kit can include a labeled probe that hybridizes to a region of human chromosome as described herein.

The kit can also include one or more additional reference or control probes that hybridize to the same chromosome or another chromosome or portion thereof that can have an abnormality associated with a particular endophenotype. A kit that includes additional probes can further include labels, e.g., one or more of the same or different labels for the probes. In other embodiments, the additional probe or probes provided with the kit can be a labeled probe or probes. When the kit further includes one or more additional probe or probes, the kit can further provide instructions for the use of the additional probe or probes. Kits for use in self-testing can also be provided. Such test kits can include devices and instructions that a subject can use to obtain a nucleic acid sample (e.g., buccal cells, blood) without the aid of a health care provider. For example, buccal cells can be obtained using a buccal swab or brush, or using mouthwash.

Kits as provided herein can also include a mailer (e.g., a postage paid envelope or mailing pack) that can be used to return the nucleic acid sample for analysis, e.g., to a laboratory. The kit can include one or more containers for the nucleic acid sample, or the nucleic acid sample can be in a standard blood collection vial. The kit can also include one or more of an informed consent form, a test requisition form, and instructions on how to use the kit in a method described herein. Methods for using such kits are also included herein. One or more of the forms (e.g., the test requisition form) and the container holding the nucleic acid sample can be coded, for example, with a bar code for identifying the subject who provided the nucleic acid sample.

In some embodiments, an in vitro screening test can comprise one or more devices, tools, and equipment configured to collect a nucleic acid sample from an individual. In some embodiments of an in vitro screening test, tools to collect a nucleic acid sample can include one or more of a swab, a scalpel, a syringe, a scraper, a container, and other devices and reagents designed to facilitate the collection, storage, and transport of a nucleic acid sample. In some embodiments, an in vitro screening test can include reagents or solutions for collecting, stabilizing, storing, and processing a nucleic acid sample.

Such reagents and solutions for nucleotide collecting, stabilizing, storing, and processing are well known by those of skill in the art and can be indicated by specific methods used by an in vitro screening test as described herein. In some embodiments, an in vitro screening test as disclosed herein, can comprise a microarray apparatus and reagents, a flow cell apparatus and reagents, a multiplex nucleotide sequencer and reagents, and additional hardware and software necessary to assay a nucleic acid sample for certain genetic markers and to detect and visualize certain genetic markers.

The present disclosure further relates to kits for using antibodies in the methods described herein. This includes, but is not limited to, kits for detecting the presence of a variant polypeptide in a test nucleic acid sample. One preferred embodiment comprises antibodies such as a labeled or labelable antibody and a compound or agent for detecting variant polypeptides in a nucleic acid sample, means for determining the amount or the presence and/or absence of variant polypeptide in the nucleic acid sample, and means for comparing the amount of variant polypeptide in the nucleic acid sample with a standard, as well as instructions for use of the kit. In certain embodiments, the kit further comprises a set of instructions for using the reagents comprising the kit.

Computer-Implemented Aspects

As understood by those of ordinary skill in the art, the methods and information described herein (genetic variation association with PML) can be implemented, in all or in part, as computer executable instructions on known computer readable media. For example, the methods described herein can be implemented in hardware. Alternatively, the method can be implemented in software stored in, for example, one or more memories or other computer readable medium and implemented on one or more processors. As is known, the processors can be associated with one or more controllers, calculation units and/or other units of a computer system, or implanted in firmware as desired. If implemented in software, the routines can be stored in any computer readable memory such as in RAM, ROM, flash memory, a magnetic disk, a laser disk, or other storage medium, as is also known. Likewise, this software can be delivered to a computing device via any known delivery method including, for example, over a communication channel such as a telephone line, the Internet, a wireless connection, etc., or via a transportable medium, such as a computer readable disk, flash drive, etc.

More generally, and as understood by those of ordinary skill in the art, the various steps described above can be implemented as various blocks, operations, tools, modules and techniques which, in turn, can be implemented in hardware, firmware, software, or any combination of hardware, firmware, and/or software. When implemented in hardware, some or all of the blocks, operations, techniques, etc. can be implemented in, for example, a custom integrated circuit (IC), an application specific integrated circuit (ASIC), a field programmable logic array (FPGA), a programmable logic array (PLA), etc.

Results from such genotyping can be stored in a data storage unit, such as a data carrier, including computer databases, data storage disks, or by other convenient data storage means. In certain embodiments, the computer database is an object database, a relational database or a post-relational database. Data can be retrieved from the data storage unit using any convenient data query method.

When implemented in software, the software can be stored in any known computer readable medium such as on a magnetic disk, an optical disk, or other storage medium, in a RAM or ROM or flash memory of a computer, processor, hard disk drive, optical disk drive, tape drive, etc. Likewise, the software can be delivered to a user or a computing system via any known delivery method including, for example, on a computer readable disk or other transportable computer storage mechanism.

The steps of the claimed methods can be operational with numerous other general purpose or special purpose computing system environments or configurations. Examples of well known computing systems, environments, and/or configurations that can be suitable for use with the methods or system of the claims include, but are not limited to, personal computers, server computers, hand-held or laptop devices, multiprocessor systems, microprocessor-based systems, set top boxes, programmable consumer electronics, network PCs, minicomputers, mainframe computers, distributed computing environments that include any of the above systems or devices, and the like.

The steps of the claimed method and system can be described in the general context of computer-executable instructions, such as program modules, being executed by a computer. Generally, program modules include routines, programs, objects, components, and/or data structures that perform particular tasks or implement particular abstract data types. The methods and apparatus can also be practiced in distributed computing environments where tasks are performed by remote processing devices that are linked through a communications network. In both integrated and distributed computing environments, program modules can be located in both local and remote computer storage media including memory storage devices. Numerous alternative embodiments could be implemented, using either current technology or technology developed after the filing date of this application, which would still fall within the scope of the claims defining the disclosure.

While the risk evaluation system and method, and other elements, have been described as preferably being implemented in software, they can be implemented in hardware, firmware, etc., and can be implemented by any other processor. Thus, the elements described herein can be implemented in a standard multi-purpose CPU or on specifically designed hardware or firmware such as an application-specific integrated circuit (ASIC) or other hard-wired device as desired. When implemented in software, the software routine can be stored in any computer readable memory such as on a magnetic disk, a laser disk, or other storage medium, in a RAM or ROM of a computer or processor, in any database, etc. Likewise, this software can be delivered to a user or a screening system via any known or desired delivery method including, for example, on a computer readable disk or other transportable computer storage mechanism or over a communication channel, for example, a telephone line, the internet, or wireless communication. Modifications and variations can be made in the techniques and structures described and illustrated herein without departing from the spirit and scope of the present disclosure.

Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The following references contain embodiments of the methods and compositions that can be used herein: The Merck Manual of Diagnosis and Therapy, 18th Edition, published by Merck Research Laboratories, 2006 (ISBN 0-911910-18-2); Benjamin Lewin, Genes DC, published by Jones & Bartlett Publishing, 2007 (ISBN-13: 9780763740634); Kendrew et al., (eds.), The Encyclopedia of Molecular Biology, published by Blackwell Science Ltd., 1994 (ISBN 0-632-02182-9); and Robert A. Meyers (ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, published by VCH Publishers, Inc., 1995 (ISBN 1-56081-569-8).

Standard procedures of the present disclosure are described, e.g., in Maniatis et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., USA (1982); Sambrook et al., Molecular Cloning: A Laboratory Manual (2 ed.), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., USA (1989); Davis et al., Basic Methods in Molecular Biology, Elsevier Science Publishing, Inc., New York, USA (1986); or Methods in Enzymology: Guide to Molecular Cloning Techniques Vol. 152, S. L. Berger and A. R. Kimmerl (eds.), Academic Press Inc., San Diego, USA (1987)). Current Protocols in Molecular Biology (CPMB) (Fred M. Ausubel, et al., ed., John Wiley and Sons, Inc.), Current Protocols in Protein Science (CPPS) (John E. Coligan, et al., ed., John Wiley and Sons, Inc.), Current Protocols in Immunology (CPI) (John E. Coligan, et al., ed. John Wiley and Sons, Inc.), Current Protocols in Cell Biology (CPCB) (Juan S. Bonifacino et al., ed., John Wiley and Sons, Inc.), Culture of Animal Cells: A Manual of Basic Technique by R. Ian Freshney, Publisher: Wiley-Liss; 5th edition (2005), and Animal Cell Culture Methods (Methods in Cell Biology, Vol. 57, Jennie P. Mather and David Barnes editors, Academic Press, 1st edition, 1998), which are all incorporated by reference herein in their entireties.

It should be understood that the following examples should not be construed as being limiting to the particular methodology, protocols, and compositions, etc., described herein and, as such, can vary. The following terms used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the embodiments disclosed herein.

Disclosed herein are molecules, materials, compositions, and components that can be used for, can be used in conjunction with, can be used in preparation for, or are products of methods and compositions disclosed herein. It is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed and while specific reference of each various individual and collective combinations and permutation of these molecules and compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a nucleotide or nucleic acid is disclosed and discussed and a number of modifications that can be made to a number of molecules including the nucleotide or nucleic acid are discussed, each and every combination and permutation of nucleotide or nucleic acid and the modifications that are possible are specifically contemplated unless specifically indicated to the contrary. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the disclosed molecules and compositions. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods, and that each such combination is specifically contemplated and should be considered disclosed.

Those skilled in the art can recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the method and compositions described herein. Such equivalents are intended to be encompassed by the following claims.

It is understood that the disclosed methods and compositions are not limited to the particular methodology, protocols, and reagents described as these can vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present disclosure which can be limited only by the appended claims.

Unless defined otherwise, all technical and scientific terms used herein have the meanings that would be commonly understood by one of skill in the art in the context of the present specification.

It should be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to “a nucleotide” includes a plurality of such nucleotides; reference to “the nucleotide” is a reference to one or more nucleotides and equivalents thereof known to those skilled in the art, and so forth.

The term “and/or” shall in the present context be understood to indicate that either or both of the items connected by it are involved. While preferred embodiments of the present disclosure have been shown and described herein, it can be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions can now occur to those skilled in the art without departing from the disclosure. It should be understood that various alternatives to the embodiments of the disclosure described herein can be employed in practicing the disclosure. It is intended that the following claims define the scope of the disclosure and that methods and structures within the scope of these claims and their equivalents be covered thereby.

EXAMPLES Example 1—Experimental Approach

In the present study, a set of genes were identified, deleterious variants within which increase susceptibility to PML. The relevant genes were discovered on the basis of a combined CNV plus sequence analysis approach. Two sets of genes were compiled (see Table 6 and corresponding description):

-   -   A. A set based on a detailed literature review of genes involved         in the immune system and JC virus biology, along with genes         described in the context of PML via case reports.     -   B. A set based on the observation of rare CNVs within the PML         cohort.

A non-redundant list of 419 genes was generated (see Table 6), which contains 245 curated from immune deficiency (immunodeficiency) reviews (Table 6, ‘Public db’), 169 identified via rare CNVs using the methods described herein (Table 6, ‘PBio’), and 6 genes that were found using both methods (Table 6, ‘Both’). See Table 6 and description below for further information).

Using this set of 419 genes, it was determined whether:

-   -   Rare CNVs were present that might explain the susceptibility to         PML;     -   Rare sequence variants (determined via whole exome sequencing         analysis—WES) were present that might explain the susceptibility         to PML;     -   Combinations of CNVs, SNVs and/or CNVs and SNVs might explain         the susceptibility;     -   Individual variants might be present at higher frequency in the         PML cohort (variant burden analysis—Tables 14, 15);     -   Total numbers of heterozygous, damaging variants were high for         any specific genes (gene burden analysis—Table 13).

In all cases, due consideration was given to:

-   -   Pathogenic/deleterious nature of the variants observed (e.g.,         whether gene function was highly likely to be affected);     -   Rarity of the variants or variant combinations (e.g., those that         would be expected to be present in 1% or less of the normal         population were considered);     -   Ethnicity of the PML cases to account for potential frequency         differences in one population subgroup vs. another. Ethnicities         (e.g., ancestry) for the PML patients are reported in Table 7.         For Sample ID identifiers beginning with ‘MVGS’, ethnicities         were not reported but all patients were from the USA and their         ethnicities were assumed to be of European (EUR) ancestry.         However, PML case MVGS811-13a is potentially of African (AFR)         ancestry on the basis of common SNVs that are also found in PML         cases known to be of AFR ancestry. In one embodiment,         ethnic-specific frequency data from the ExAC database was used         to assess relative frequencies of variants found in PML patients         vs. an unselected population (ExAC subjects). ExAC ethnicities         were designated as follows: African/African American (AFR),         Latino (LAT, also known as AMR), East Asian (EAS), Finnish         (FIN), Non-Finnish European (EUR, also known as NFE), South         Asian (SAS), and Other (OTH). For some PML cases reported in         Table 7, the ethnicities were alternately reported as         Subsaharan, North African (MGB), Caribbean (CAR), or Hispanic         (HISP). For interpretation of variants found in these patients,         the assignments of ancestry using ExAC db designations were as         follows: AFR=MGB or Subsaharan; LAT=CAR or HISP. Ancestry was         unknown for two PML cases (PML02 and PML28) and, for frequency         interpretation purposes (using ExAC db), they were assumed to be         of European (EUR) ancestry.

While the primary genetic mechanism that was considered was autosomal recessive (AR) inheritance, a number of solutions were based on autosomal dominant (AD) inheritance but only in cases for which prior evidence was found that heterozygous variants in the relevant gene had previously been associated with an immune deficiency syndrome. It can be appreciated by those skilled in the art that some genes may contain both AR and AD model pathogenic variants (e.g., see Table 6 entries marked as ‘AD AR’ in the ‘Disease Model’ column).

For AR inheritance (˜40% of genes in Table 6 fall into this category, AR or AD AR), the following were considered:

-   -   Homozygous or compound heterozygous gene-disruptive CNVs;     -   Homozygous or compound heterozygous sequence variants; e.g.         single nucleotide variants (SNVs). Compound heterozygosity was         only inferred when either phasing was available or one of the         pairs of SNVs was itself homozygous;     -   Compound heterozygosity for a CNV and SNV. Such calls were only         possible in cases for which the SNV was in trans to a deletion         (e.g., DUSP16 SNV in Table 10 and the CNV in Table 1).

Example 2—Copy Number Variant (CNV) Analysis

The data presented herein was generated on the basis of a comparison of copy number variants (CNVs) identified in 2 cohorts:

-   -   1) 1,005 Normal individuals (Normal Variation Engine—NVE);     -   2) 71 Progressive Multifocal Leukoencephalopathy (PML) cases         along with 6 Human Immunodeficiency Virus (HIV) cases without a         diagnosis of PML (in order to aid in distinguishing germline         variants vs. acquired variants that result from HIV infection).         Total cohort size=77.

Genomic DNA Sample Hybridization—NVE and PML, HIV Cohorts

Genomic DNA samples from individuals within the Normal cohort (NVE ‘test’ subjects, also referred to as ‘NVE cases’ in some tables herein) and from the PML, HIV cohort (PML, HIV ‘test’ subjects) were hybridized against a single, sex-matched reference individual. Reference DNA samples were labeled with Cy5 and test subject DNA samples were labeled with Cy3. After labeling, samples were combined and co-hybridized to Agilent 1M feature oligonucleotide microarrays, design ID 021529 (Agilent Product Number G4447A) using standard conditions (array Comparative Genomic Hybridization—aCGH). Post-hybridization, arrays were scanned at 2 μm resolution, using Agilent's DNA microarray scanner, generating tiff images for later analysis.

All tiff images were analyzed using Agilent Feature Extraction (FE) software, with the following settings:

-   -   Human Genome Freeze:hg18:NCBI36:Mar2006     -   FE version: 10.7.3.1     -   Grid/design file: 021529 D F 20091001     -   Protocol: CGH 107 Sep09

This procedure generates a variety of output files, one of which is a text-tab delimited file, containing 1,000,000 rows of data, each corresponding to a specific feature on the array. This *.txt file was used to perform CNV calling using DNAcopy, an open source software package implemented in R via BioConductor (http://www.bioconductor.org/packages/release/bioc/html/DNAcopy.html). Heterozygous losses (het loss), homozygous losses (hom loss) or gains were determined according to a threshold log 2ratio, which was set at:

-   -   hom loss min=−1000;     -   hom loss max=−2;     -   het loss min=−2;     -   het loss max=−0.5;     -   gain min=0.5;     -   gain max=1000;

With very few exceptions, all CNVs with a log 2ratio value between −0.5 and +0.5 were not considered. All log 2ratio values were determined according to Cy3/Cy5 (Test/Reference). A minimum probe threshold for CNV-calling was set at 2 (2 consecutive probes were sufficient to call a CNV). A CNV list was generated for each individual in the 3 cohorts (NVE, PML, and HIV).

Using custom scripts, CNVs identified in the NVE and PML cohorts (many of which appeared in multiple individuals) were (separately) ‘merged’ into master lists of non-redundant CNV-subregions, according to the presence or absence of the CNV-subregion in individuals within the cohort. Using this approach, the NVE-master lists have:

-   -   7778 het loss     -   653 horn loss     -   4862 gain distinct CNV-subregions, respectively. The PML+HIV         cohort of 77 individuals master lists contained:     -   2523 het loss     -   314 horn loss     -   1639 gain         distinct CNV-subregions, respectively.

Those skilled in the art can appreciate that CNVs can be acquired in an individual's genome that are not inherited. Such ‘acquired CNVs’ often occur in a tissue specific manner, such as in solid tumors compared to a patient's normal tissue. In blood-derived genomic DNA samples, which are what was used for both the NVE and PML subjects in the studies described herein, acquired CNVs can be the result of blood cancers such as leukemia and lymphoma, but also due to HIV infection. Many of the PML cases in this study had HIV as their primary disease (see Table 7). In order to aid in the interpretation of acquired vs. germline CNVs, an HIV sub-cohort of 6 cases was included in the primary, genome-wide CNV comparison but rare CNVs in the 6 HIV (non-PML) cases were not considered as relevant to PML susceptibility. The purpose of generating data on the 6 HIV cases was to determine whether some changes seen in PML patients who developed the disorder on a background of HIV (PML/HIV) were likely related to the underlying HIV and not the PML susceptibility itself. In other words, the HIV cases served as a general control for the large number of PML/HIV cases.

For example, consider 3 individuals within the NVE cohort with the following hypothetical CNVs: Chr1:1-100,000; Chr1:10,001-100,000; and Chr1:1-89,999. In the master list, these would be merged into 3 distinct CNV subregions, as follows:

-   -   CNV-subregion 1 Chr1:1-10,000 Subjects A, C     -   CNV-subregion 2 Chr1:10,001-89,999 Subjects A, B, C     -   CNV-subregion 3 Chr90,000:1-100,000 Subjects A, B         Comparison of the corresponding NVE and PML master lists of         CNV-subregions was performed (het loss versus het loss, horn         loss versus horn loss and gain versus gain), resulting in a         combined file with totals for NVE and PML for each distinct         CNV-subregion in the study.

The data are subsequently curated as follows (The example calculation below was based on an original PML cohort of 80 cases, of which 6 are non-PML HIV controls and 3 PML cases that were duplicate samples. In some instances, the OR and FET values reported in Table 2 were used as ‘relative’ guidelines when considering the relevance of a CNV. In nearly all instances, a CNV was considered as a potential cause or contributing factor to PML if it was absent from the NVE database of CNVs).

-   -   Annotation using custom designed scripts in order to attach         relevant information to each CNV region regarding overlap with         known genes and exons, overlap with genes involved in the immune         system and overlap with regulatory regions, including         transcription factor binding sites.     -   A calculation of the odds ratio (OR) and Fisher's Exact test         (FET) for each CNV-subregion, according to the following         formula:         -   OR=(PML/(77-PML))/(NVE/(1005-NVE))         -   where:         -   PML=number of PML individuals with CNV-subregion of interest         -   NVE=number of NVE individuals with CNV-subregion of interest

As an illustrative example, consider the CNV subregion gain involving chr2:55764753-55771586, which is found in 3 individuals in the PML cohort and 1 individual in the NVE cohort (see Table 2). The OR is: (3/74)/(1/1004)=40.7

Note that, by one convention, if either of NVE or PML=0, a value of 0.5 is added to all 4 entries in the main formula above, in order to avoid dealing with infinities (see Deeks and Higgins, Statistical algorithms in Review Manager 5, Statistical Methods Group of The Cochrane Collaboration, (2010)). This has the effect of artificially lowering OR values in cases where no individuals within the NVE have the CNV. This method is applicable to all the calculations in Table 2. This method is also used when calculating the Fisher's 2-tailed Exact Test (FET) in the event that any one of the variables is zero. For convenience in analysis, the sub-cohort of 6 HIV (non-PML) cases were retained in Table 2. Therefore, the OR values reported in Table 2 are slightly different from the OR calculations for the actual number of PML cases (n=71). Using the example above for a CNV-subregion gain involving chr2:55764753-55771586, the actual OR using 71 PML cases vs. 1005 NVE subjects was: (3/68)/(1/(1004)=44.29. In some instances, a non-PML HIV control (see Table 11, identified as 3280, 3281, 3283, 3284, 3285, and 3286) is found to have a CNV of potential relevance in PML subjects. This can also impact the OR calculation. For example, for CNV-subregion loss chr19:55247874-55250186 the OR in Table 2 is listed as 17.38 but one case is a non-PML HIV control (Table 11, PML70 control=3280). For this example, the actual OR using 71 PML cases vs. 1005 NVE subjects, and excluding the non-PML HIV case, was: (4/67)/(4/(1001)=14.94.

The CNV-subregions/genes that are listed herein (e.g., in one or more of Tables 1-4), fulfill one of the following criteria:

-   -   Strong biology linking the gene that a CNV-subregion impacts or         is near, with known immune deficiency pathways/mechanisms or         biology in PML (e.g., JC virus related biology). That is, in         some cases, statistical evidence is lacking but does not exclude         the CNV-subregion as a candidate;     -   Statistical analysis combined with medium to strong biology         (e.g., links in the peer-reviewed literature to PML, JC virus,         host defense, immune deficiency, or neuropathology) without         obvious biological connection (best FET in this category was         3.25E-10);

It can be appreciated by those skilled in the art that the number of PML candidate CNV-subregions, irrespective of category, may increase or decrease as additional PML cohorts are analyzed.

Example 3—Whole Exome Sequencing (WES) and Case Level Analysis

WES data was obtained on a total of 70 PML cases (non-PML HIV cases were not sequenced—they were used simply to help in the interpretation of complex CNVs observed in PML patients who also had HIV).

Variant annotation reports were further interrogated against the full set of genes detailed above. Synonymous variants and variants predicted to be modifiers (outside coding regions) were not considered. For all other variants, further filtering was performed so that only those predicted by at least one in silico prediction algorithm (e.g., Polyphen2, SIFT, MutationTaster) to be pathogenic were considered for further evaluation. Finally, only variants or variant combinations that would be expected to be present in 1% or less of the normal population were evaluated for case level analysis (Tables 7-10). Data from the Exome Aggregation Consortium (ExAC) was used to obtain ethnic-specific frequency data for variants under consideration (see, Lek et al., Nature, 17; 536(7616):285-91) (2016)).

Example 4—Description of Sequence Data

The sequence file 56969-701.601 ST25.txt contains genomic sequence information for (in the following order):

A. All distinct CNVs listed in Table 1;

B. The full genomic extent of the transcripts listed in Table 4;

C. Sequence variants detailed in Table 5.

D. The full genomic extent of the transcripts listed in Table 12

Note that:

1. SEQ ID 1-172 are the CNV sequences from Table 1;

2. SEQ ID 173-455 are the transcript sequences from Table 4;

3. SEQ ID 1000-1329 are the sequence variants from Table 5;

4. SEQ ID 1500-2177 are the transcript sequences from Table 12.

Examples of sequences submitted:

Sequence entry starts:

TABLE 1 SEQ ID 1 = 49,653 bp CNV (het loss) at chr1:1086119-1135772 involving genes MIR200A, MIR200B, MIR429, TNFRSF18, TTLL10: <210> 1 <211> 49654 <212> DNA <213> Homo sapiens <400> 1 cttctggggt ctaaggccag aagtgacctt tcttctcacg gaggcacccc cacatcacag    60 gccccaagct cccaccagga gtccccaggc agcaggtttt ccaccacagc cgggaagagc   120 cccgccttca ccacccacca ccagccaatc ccgagaccac cgaagccccc agaccgggcc   180 ........................................................(sequence  truncated for brevity) gattcccgca cggccgggga cggccccagg gccttgggag cgtctgtgga cacctgtggt 49560 gtgggccgag gagctgggag ctcatctgaa cacgccagca ctcgcgcatc cacgctgctg 49620 gcggatgcct gggtttctcc actgtggggc cacg 49654 Sequence entry ends. Sequence entry starts:

TABLE 4 SEQ ID 173 = MIR200B, transcript NR 029639, which is 95 bp in length: <210> 173 <211> 95 <212> DNA <213> Homo sapiens <400> 173 ccagctcggg cagccgtggc catcttactg ggcagcattg gatggagtca ggtctctaat 60 actgcctggt aatgatgacg gcggagccct gcacg 95 Sequence entry ends. Sequence entry starts:

TABLE 5 SEQ ID 1148 = chr 9:304628 reference allele = G; alternate allele = A <210> 1148 <211> 40 <212> DNA <213> Homo sapiens <220> <221> variant <222> (20)..(20) <223> G->A <400> 1148 tttaaaaaga ctggatctcg aaaagatttt cacaagacgc 40 Sequence entry ends. Sequence entry starts:

TABLE 12 SEQ ID 1500 = ACADM, transcript NM 000016, which is 39,313 bp in length: <210> 1500 <211> 39313 <212> DNA <213> Homo sapiens <400> 1500 cgcaagtccc cccaccgttc agcgcaaccg ggccctccca gccccgccgc cgtccccctc    60 ccccgccctg gctctctttc cgcgctgcgg tcagcctcgg cgtcccacag agagggccag   120 .......................................................(sequence truncated for brevity) gtaatagtgt atatttcttg tatttactat gatgaaaaaa ggtcgtttta attttgaatt 39240 gaataaagtt acctgttcat tttttattag atattttaaa gacttcagaa aatataaata 39300 tgaaataatt taa  39313 Sequence entry ends.

Example 5

Those skilled in the art can appreciate that genes can be impacted by acquired or germline genetic variants (e.g., CNVs), wherein each gene has the potential to contain genetic variants that are acquired (e.g., via a disease process such as HIV infection, or cancers such as leukemia and lymphoma) or present in the germ line (e.g., inherited from a parent or are de novo, e.g. not inherited from a parent). In FIG. 1, the PRKCB gene was impacted by germ line variants in 2 PML cases and acquired variants in 6 PML cases. The invention described herein is focused on detection of germline variants that are present in PML patient genomes. Therefore, no solutions/explanations for a given patient's PML was based on an acquired CNV, although another PML patient could potentially be ‘solved’ by one or two germline rare variants impacting the gene.

For this PRKCB example, no CNV-based solutions were found (an AR model was assumed), but 1 SNV solution is reported in Table 8 (het SNV, an AD model is assumed for this PML case). Further supporting evidence was assessed for the PRKCB gene by performing String analysis (high confidence=0.7, 1st shell=up to 10 interactors; string-db.org; see Szklarczyk et al., (2015), and references therein). String analysis showed that PRKCB interacts with PML-419 genes CARD11, IKBKB, and RBCK1 (see Table 6).

In FIG. 2, both TNFRSF13C and CENPM are disrupted and/or gained by a set of acquired CNV gains. Acquired CNVs can be very complex, such as the high copy number gains often identified in tumor-derived DNA samples (as compared to the patient's normal genome). In the PML gene discovery described herein, blood-derived genomic DNA obtained from several PML-diagnosed HIV patients, or PML cases with a primary disease of leukemia and lymphoma (reported as ‘Other’ in Table 7), showed complex genomic changes (e.g., gains exhibiting a dup-trip-dup pattern). In some PML cases, the acquired gains passed the log 2 ratio cutoff (>0.5) that was selected for this study, but in other PML cases the log 2 ratios for the gains were <0.5 and this data was filtered out from the main analyses that were performed to ascertain rare germline CNVs.

In one embodiment of the invention, a set of 6 non-PML HIV cases (3 African ancestry, 3 European ancestry) were used to aid in the interpretation of whether a CNV was an acquired or germline event. The non-PML ‘PML cases’ are labeled with ‘ control’ in Table 11 and correspond to ‘PML Case ID’ numbers 3280, 3281, 3283, 3284, 3285, and 3286. While some CNVs are reported in Tables 1 and 2 for this set of non-PML control HIV subjects, none of these genetic findings were used to nominate a gene discovered on the basis of rare CNVs (as compared to the NVE db) as a potential PML gene (PBio genes reported in Table 6). In other words, these rare CNVs were only used to aid in determining if a particular genomic region containing multiple overlapping CNVs was potentially due to an acquired genetic event. Those skilled in the art can appreciate that the set of experiments described herein do not necessarily fully rule in or out that a given genomic region contained only acquired CNVs vs. only germline CNVs (e.g. it's possible that the same region can contain an acquired CNV in one individual and a germline CNV in another).

For the CNV data shown in FIG. 2, both the TNFRSF13C and CENPM genes were included in PML-419 gene list (Table 6) on the basis of their immune or neurological related biology reported in the literature. No CNV or SNV PML solutions were found for these two genes, but String analysis (high confidence=0.7, 1st shell=up to 10 interactors) shows that TNFRSF13C interacts with PML-419 genes TRAF3 (Table 7 solution) and TNFRSF13B (Table 8 solution), as well as BTK (a known PML gene, see Table 6).

FIG. 3 shows another example of a gene that is impacted by both germline and acquired CNVs. While no PML cases were solved on the basis of the acquired or germline CNVs shown to impact the PKHD1 gene, nomination of this gene to Table 6 on the basis of its biology resulted in finding 3 potential alternate solutions (AR model) for 3 other PML cases (see Table 8). However, String analysis (high confidence=0.7, 1st shell=up to 10 interactors) did not reveal any PML-419 gene interactions with PKHD1.

Example 6

Those skilled in the art can appreciate that an AR disease model would involve ascertaining whether both alleles (for a gene or genetic locus) are impacted by a genetic variant in individuals affected by the disorder. The types of genetic variants can be SNVs, CNVs, indels, etc. In the study describe herein, if an AR disease model was invoked for a gene (see Table 6), we assessed the PML patient's CGH data for CNVs (heterozygous or homozygous) and their exome data for SNVs (heterozygous or homozygous). Thus, each patient may be solved for one of the PML-419 genes (Table 6) with one of the following scenarios: homozygous deletion, homozygous duplication (log 2 ratio will appear comparable to that typically found for triplications), homozygous SNV, compound heterozygous SNVs, compound heterozygous CNVs, or compound heterozygous SNV and CNV. Those skilled in the art know that, for an AR disease mechanism, a pathogenic SNV or CNV may have appreciable frequency in the general population (e.g., up to 1% frequency) with little to no impact on the individual's health, but when present with a second pathogenic variant on the other allele, can cause disease.

FIG. 4 shows an example of an intronic loss impacting the BMPR2 gene. Patient PML29 was found to have a homozygous deletion, whereas as patients PML58 and MVGS811-13a have a heterozygous deletion. Assuming an AR disease model, no SNV solutions were found for this gene; however, PML29 is potentially solved due to the homozygous deletion that was detected. While immune-related biology is reported for studies on BMPR2 (see Table 6), String analysis (high confidence=0.7, 1st shell=up to 10 interactors) did not reveal any PML-419 gene interactions with BMPR2.

FIG. 5 shows an example of an exonic gain that disrupts the COMMD6 gene. Two PML patients were found to have homozygous duplications of this CNV. Interestingly, while String analysis (high confidence=0.7, 1st shell=up to 10 interactors) did not reveal any PML-419 gene interactions with COMMD6, recent studies (see Table 6, PMIDs 25355947 and 27441653) show a potential link between COMMD6 and known PML gene WAS via the WASH gene.

FIG. 6 shows an example of an exonic gain that disrupts the KCTD7 gene and its right breakpoint is upstream of RABGEF1 (e.g. one or both genes may be causing/contributing to PML). A recently annotated non-coding RNA (see hg19 assembly, LOC100996437) may also be impacted by this CNV. Both genes have immune and neurological links (see Table 6) and since patient PML29 has a homozygous duplication, it was added as a PML solution in Table 7. String analysis (high confidence=0.7, 1st shell=up to 10 interactors) did not reveal any PML-419 gene interactions for either gene, but they are linked together in a joint String analysis.

FIG. 7 shows an example of a gain that disrupts FPR2 (left breakpoint) and ZNF616 (right breakpoint, gene not labeled), and other genes are fully encompassed by this CNV. There is strong supporting biology for FPR2 (see Table 6) and it is listed as a PML solution in Table 7. String analysis (high confidence=0.7, 1st shell=up to 10 interactors) did not reveal any PML-419 gene interactions for FPR2, but a joint analysis of Table 7 genes did reveal an interaction (see FIG. 13).

FIG. 8 shows an example of an exonic loss impacting the PIK3CD and PIK3CD-AS1 genes.

Patient MVGS811-13a has a homozygous deletion and is reported as a solution in Table 7 based on the strong immune-related biology for PIK3CD (see Table 6). String analysis (high confidence=0.7, 1st shell=up to 10 interactors) reveals PML-419 gene interactions for PTEN and PIK3R1.

Example 7

A subset of the rare CNVs found in our PML study were located in intergenic regions. While those skilled in the art can appreciate that intergenic variants (CNVs, SNVs, etc.) can have long range effects on the expression of genes (e.g., gene regulatory elements can be located several kilobases away from the genes under their influence), in our study we assumed that intergenic CNVs were potentially impacting one or both adjacent genes if they were located <˜100 Kb away, either upstream or downstream. The ENCODE project has revealed a wealth of information, such as transcription factor binding sites, and rare CNVs that were identified in the study herein were checked for their potential impact on these sites (hg19 assembly ENCODE annotation was checked) and were often found to impact transcription factor binding sites and/or were located in conserved DNA regions.

FIG. 9 shows an intergenic gain that is upstream of CD180. Patient MVGS995-4a has a homozygous duplication and, while not considered as a PML solution in Table 7, is potentially an alternate solution that may be causing or contributing to the patient's PML based on altered expression of CD180. The gene has immune-related biology (see Table 6) and String analysis (high confidence=0.7, 1st shell=up to 10 interactors) reveals a PML-419 gene interaction with PLCG2 (see Table 7, 2 PML cases have a solution for this gene).

FIG. 10 shows an intergenic loss that is upstream of VDAC1. Patient PML30 has a homozygous deletion and, while not considered as a PML solution in Table 7, is potentially an alternate solution that may be causing or contributing to the patient's PML based on altered expression of VDAC1. String analysis (high confidence=0.7, 1st shell=up to 10 interactors) did not reveal any PML-419 gene interactions for VDAC1.

FIG. 11 shows an intergenic loss that is downstream of EGR1 and ETF1. Patient PML69 has a homozygous deletion and, based on links for EGR1 to PML-419 genes (Table 6) and its proximity to EGR1 (˜4 Kb away), it was added as a potential PML solution in Table 7. String analysis (high confidence=0.7, 1st shell=up to 10 interactors) reveals PML-419 gene interactions with JUN, PTEN, and TP53), but nothing of note was found for String analysis of ETF1.

FIG. 12 shows an intergenic loss that is upstream of ITSN2. Patient PML65 has a homozygous deletion and, based on links for ITSN2 to a known PML gene (WAS) in the PML-419 gene list (Table 6), it was added as a potential PML solution in Table 7. Interestingly, another PML case was found to have a rare homozygous SNV in ITSN2, so this gene has 2 PML solutions reported in Table 7. String analysis (high confidence=0.7, 1st shell=up to 10 interactors) did not reveal any PML-419 gene interactions.

Example 8

Pathway analyses, such as protein-protein interactions, are providing valuable insights into the underlying biology for complex diseases. While PML is a very rare disease that requires several concurrent factors (e.g., infection by the JC virus), multiple genes may be independently causing or increasing the risk of developing this neurodegenerative disorder based on the presence of a genetic variant in a given gene (e.g., a heterozygous variant wherein one deleterious variant is present on the maternally or paternally inherited allele, a homozygous variant wherein the same deleterious variant is present on both alleles, or compound heterozygous variants wherein a pair of deleterious variants are present but one is found on the maternally inherited allele and the other is found on the paternally inherited allele). As hypothesized, presence of an immune deficiency genetic disorder was another prerequisite. Indeed, in the PML study described herein, 43 genes were proposed as solutions for 61 of 71 PML cases (see Table 7) that were assessed using array CGH and whole exome sequencing. Numerous algorithms and associated databases have been developed to investigate molecular pathways, such as String (see, Szklarczyk et al., (2015), and references therein).

FIG. 13 shows an example of String analysis performed on the 43 genes considered as PML solutions on the basis of an AD or AR disease model. A series of interactions were found for 21 of 43 genes, and in several instances this included interactions for genes implicated in 2 or more PML cases that are reported in Table 7 (9 cases for TNFRSF11A, 4 cases for PLCG2, 3 cases for ZAP70 and NOD2, and 2 PML cases for TICAM1).

Example 9

To determine the likelihood that a randomly selected individual would harbor one of the variants described herein, the following analysis was performed: For each variant or combination of variants, the ethnic-specific frequency quoted in Table 7 was used to determine the probability that a randomly selected individual of the same ethnicity would be expected not to harbor the variant or combination of variants. The product of all such probabilities was calculated (e.g., the probability that a randomly selected individual would not harbor any of the variants) and subtracted from 1, yielding the probability that a random individual would harbor at least one of the variants. It was found that, for HIV cases, the probability of a random individual harboring at least one of the variants was ˜5%, which is consistent with the pre-HAART risk of PML in the context of HIV. For non-HIV cases (mostly MS/NTZ), the risk was ˜1%, which, again, is consistent with the risk of PML in MS/NTZ, especially after long-term therapy.

These analyses support the notion that the frequencies of the variants identified as relevant to PML risk are consistent with the actual observed risks for unselected individuals. The analyses are predicated on the reasonable assumption that there is no PML-relevant connection with the risk of developing HIV (an acquired infection) and/or MS (e.g., this implies that treatment of healthy individuals with Natalizumab, for example, would result in similar risks of PML). Any deviations (e.g., variants found in a slightly higher number of normal individuals than expected according to the numbers actually observed to be affected by PML) may be due to: penetrance (e.g., not everyone with the variants will be at maximal risk of PML); the assumption that individuals with MS, HIV and other underlying conditions represented a normal (e.g., with respect to PML risk) cross-section of the general population, prior to developing the underlying disorders HIV, MS etc; and under ascertainment of PML, even in patients with HIV, MS/NTZ.

Example 10—Tables Referenced in this Study

TABLE 1 CNVs of interest in this study Original Original Original PML RefSeq Gene SEQ Chr CNV Start CNV Stop CNV Size CNV Type Case ID Symbol ID 1 1086119 1135772 49653 het loss 3009 MIR200A 1 MIR200B MIR429 TNFRSF18 TTLL10 1 9634094 9635206 1112 hom loss 3009 PIK3CD 2 1 12018512 12032581 14069 gain 3205 3 1 19593401 19602807 9406 het loss 3203 CAPZB 4 1 21695957 21700243 4286 het loss 3161 5 1 24364786 24391166 26380 gain 3199 IFNLR1 6 1 28666669 28737671 71002 gain 3161 PHACTR4 7 RCC1 SNHG3 1 49372054 49380088 8034 het loss 3145 AGBL4 8 1 153816159 153827698 11539 het loss 3168 9 1 205607255 205610341 3086 gain 3007 10 1 215760485 215762451 1966 het loss 3117 GPATCH2 11 1 215866737 215869900 3163 het loss 3151 GPATCH2 12 2 10352668 10356083 3415 het loss 3007 13 2 24457024 24462631 5607 hom loss 3204 14 2 38468717 38471950 3233 het loss 3175 15 2 38516138 38524237 8099 het loss 3151 16 2 38726517 38731845 5328 het loss 3159 17 2 40620890 40624089 3199 het loss 3202 18 2 46631006 46643501 12495 gain 3145 RHOQ 19 2 55764753 55790559 25806 gain 3143 PNPT1 20 2 55764753 55790559 25806 gain 3193 PNPT1 20 2 55764753 55790559 25806 gain 3282 PNPT1 20 2 55764753 55790559 25806 gain 3143 PNPT1 20 2 55764753 55790559 25806 gain 3193 PNPT1 20 2 55764753 55790559 25806 gain 3282 PNPT1 20 2 55764753 55790559 25806 gain 3143 PNPT1 20 2 55764753 55790559 25806 gain 3193 PNPT1 20 2 55764753 55790559 25806 gain 3282 PNPT1 20 2 71190677 71200120 9443 het loss 3175 MCEE 21 2 71190677 71200120 9443 het loss 3175 MCEE 21 2 71191311 71200120 8809 het loss 3204 MCEE 22 2 71198108 71200120 2012 het loss 3143 MCEE 23 2 71190677 71200120 9443 het loss 3175 MCEE 21 2 71198108 71200120 2012 het loss 3193 MCEE 23 2 71198108 71200120 2012 het loss 3200 MCEE 23 2 71191311 71200120 8809 het loss 3204 MCEE 22 2 74773432 74913493 140061 gain 3118 HK2 24 2 105418748 105435274 16526 het loss 3193 FHL2 25 2 110182348 110210249 27901 gain 3174 MALL 26 MIR4267 MIR4436B1 MIR4436B2 2 127823042 127828410 5368 het loss 3273 27 2 134911636 134914254 2618 het loss 3273 MGAT5 28 2 203005216 203019933 14717 het loss 3009 BMPR2 29 2 203005216 203019933 14717 het loss 3192 BMPR2 29 2 203005216 203019933 14717 hom loss 3152 BMPR2 29 2 230212897 230216339 3442 het loss 3154 DNER 30 3 122979920 122994402 14482 gain 3202 IQCB1 31 4 26565071 26566345 1274 het loss 3010 STIM2 32 4 26565071 26566345 1274 het loss 3125 STIM2 32 4 26565071 26566345 1274 het loss 3168 STIM2 32 4 26565071 26566345 1274 het loss 3282 STIM2 32 4 26565071 26566345 1274 het loss 3284 STIM2 32 4 26565071 26566345 1274 hom loss 3273 STIM2 32 4 54838623 54873909 35286 gain 3153 PDGFRA 33 4 90791460 90843887 52427 gain 3168 34 4 90800863 90808258 7395 het loss 3009 35 4 90800863 90808258 7395 het loss 3284 35 5 45331278 46150784 819506 gain 3157 HCN1 36 5 49771219 49774457 3238 gain 3273 EMB 37 5 66619415 66636116 16701 gain 3010 38 5 78480194 78497296 17102 gain 3205 39 5 78497296 78531091 33795 gain 3132 40 5 78497296 78521408 24112 gain 3185 41 5 78497296 78531091 33795 gain 3132 40 5 78497296 78521408 24112 gain 3185 41 5 78500552 78526637 26085 gain 3205 42 5 78497296 78531091 33795 gain 3132 40 5 78500552 78526637 26085 gain 3205 42 5 78497296 78531091 33795 gain 3132 40 5 83490494 83495169 4675 het loss 3204 EDIL3 43 5 133372071 133379727 7656 hom loss 3153 44 5 137836466 137843309 6843 hom loss 3279 45 5 150159466 150202601 43135 het loss 3117 46 5 150159466 150204134 44668 het loss 3180 47 5 150159466 150202601 43135 het loss 3199 46 5 150159466 150204134 44668 het loss 3278 47 5 150159466 150202601 43135 het loss 3117 46 5 150159466 150204134 44668 het loss 3180 47 5 150159466 150202601 43135 het loss 3199 46 5 150159466 150204134 44668 het loss 3278 47 5 150159466 150202601 43135 het loss 3117 46 5 150159466 150204134 44668 het loss 3180 47 5 150159466 150202601 43135 het loss 3199 46 5 150159466 150204134 44668 het loss 3278 47 5 150185190 150201145 15955 hom loss 3009 48 5 150185190 150201145 15955 hom loss 3143 48 5 150185190 150202601 17411 hom loss 3152 49 5 150185190 150202601 17411 hom loss 3154 49 5 150185190 150202601 17411 hom loss 3193 49 5 150159466 150201145 41679 hom loss 3196 50 5 150185190 150201145 15955 hom loss 3281 48 5 150185190 150201145 15955 hom loss 3009 48 5 150185190 150201145 15955 hom loss 3143 48 5 150185190 150202601 17411 hom loss 3152 49 5 150185190 150202601 17411 hom loss 3154 49 5 150185190 150202601 17411 hom loss 3193 49 5 150159466 150201145 41679 hom loss 3196 50 5 150185190 150201145 15955 hom loss 3281 48 5 150185190 150202601 17411 hom loss 3152 49 5 150185190 150202601 17411 hom loss 3154 49 5 150185190 150202601 17411 hom loss 3193 49 5 150185190 150204134 18944 het loss 3132 51 5 150159466 150204134 44668 het loss 3180 47 5 150202601 150204134 1533 het loss 3196 52 5 150191322 150204134 12812 het loss 3273 53 5 150185190 150204134 18944 het loss 3277 51 5 150159466 150204134 44668 het loss 3278 47 5 150185190 150204134 18944 het loss 3280 51 5 150185190 150204134 18944 het loss 3282 51 5 179590681 179626660 35979 het loss 3172 MAPK9 54 6 2882577 2947403 64826 het loss 3196 DKFZP686I15217 55 NQO2 SERPINB6 6 2964646 2966011 1365 het loss 3193 HTATSF1P2 56 NQO2 6 51766024 51773250 7226 het loss 3167 PKHD1 57 6 51952217 51969378 17161 gain 3127 PKHD1 58 6 51952217 51969378 17161 gain 3127 PKHD1 58 6 51953476 51965723 12247 gain 3205 PKHD1 59 6 51952217 51969378 17161 gain 3127 PKHD1 58 6 74396294 74404837 8543 het loss 3009 SLC17A5 60 6 74396294 74398409 2115 het loss 3160 SLC17A5 61 6 74396294 74404837 8543 het loss 3009 SLC17A5 60 6 86416979 86431527 14548 het loss 3197 62 6 91131823 91135670 3847 het loss 3171 63 6 107882367 107890605 8238 het loss 3201 PDSS2 64 6 166418511 166422386 3875 het loss 3125 65 6 166418511 166422386 3875 het loss 3163 65 6 166418511 166422386 3875 het loss 3192 65 6 166418511 166422386 3875 het loss 3193 65 6 166418511 166422386 3875 het loss 3194 65 6 166418511 166422386 3875 het loss 3200 65 6 166418511 166422386 3875 het loss 3205 65 6 166418511 166422386 3875 het loss 3280 65 6 166418511 166422386 3875 het loss 3281 65 6 166418511 166422386 3875 het loss 3284 65 6 166418511 166422386 3875 hom loss 3009 65 6 166418511 166422386 3875 hom loss 3152 65 6 166418511 166422386 3875 hom loss 3175 65 7 65741238 65768682 27444 gain 3152 KCTD7 66 7 65741238 65768682 27444 gain 3202 KCTD7 66 7 157174966 157177843 2877 het loss 3009 PTPRN2 67 7 157425841 157496238 70397 gain 3189 PTPRN2 68 7 158000082 158024569 24487 het loss 3279 PTPRN2 69 7 158000082 158024569 24487 het loss 3279 PTPRN2 69 7 158000082 158024569 24487 het loss 3279 MIR595 69 PTPRN2 8 23103186 23125443 22257 het loss 3140 TNFRSF10A 70 8 39914488 39919594 5106 het loss 3126 IDO2 71 8 79905654 79910286 4632 het loss 3159 72 8 99790200 99799839 9639 het loss 3006 STK3 73 8 102049360 102064431 15071 het loss 3173 74 8 102049360 102064431 15071 het loss 3175 74 8 102049360 102064431 15071 het loss 3282 74 9 571398 584647 13249 het loss 3006 KANK1 75 9 571398 584647 13249 het loss 3006 KANK1 75 9 580722 598488 17766 het loss 3200 KANK1 76 9 580722 598488 17766 het loss 3282 KANK1 76 9 580722 598488 17766 het loss 3200 KANK1 76 9 580722 598488 17766 het loss 3282 KANK1 76 9 634039 637589 3550 het loss 3273 KANK1 77 9 634039 637589 3550 het loss 3282 KANK1 77 9 74050088 74059447 9359 het loss 3165 GDA 78 9 93140394 93447826 307432 gain 3198 AUH 79 MIR3163 M1R3910-1 MIR3910-2 NFIL3 9 118564159 118575633 11474 gain 3193 ASTN2 80 9 118612694 118664593 51899 het loss 3144 ASTN2 81 9 119220847 119233078 12231 gain 3005 82 10 899657 1071401 171744 gain 3161 GTPBP4 83 IDI2 IDI2-AS1 LARP4B 10 76217585 76411591 194006 gain 3179 KAT6B 84 10 116000069 116004388 4319 gain 3010 VWA2 85 11 14677012 14689025 12013 het loss 3199 PDE3B 86 11 34608313 34615878 7565 het loss 3117 EHF 87 11 62382087 62398462 16375 het loss 3205 SLC3A2 88 11 76631014 76643625 12611 het loss 3193 GDPD4 89 12 11616557 12422129 805572 het loss 3126 ETV6 90 12 12435301 12778142 342841 het loss 3126 APOLD1 91 CDKN1B CREBL2 DUSP16 GPR19 LOH12CR1 12 12968705 12971310 2605 gain 3127 92 12 91786998 94313682 2526684 het loss 3126 EEA1 93 LOC643339 12 91786998 94313682 2526684 het loss 3126 LOC643339 93 MRPL42 NUDT4 NUDT4P1 SOCS2 SOCS2-AS1 UBE2N 12 91786998 94313682 2526684 het loss 3126 CCDC41 3 CRADD 9 PLXNC1 12 111061085 111064486 3401 het loss 3004 TRAFD1 94 13 40939924 41026908 86984 gain 3140 RGCC 95 13 75006025 75016304 10279 gain 3009 COMMD6 96 13 75006025 75016304 10279 gain 3152 COMMD6 96 13 91811087 91814369 3282 het loss 3143 GPC5 97 13 91811087 91811118 31 hom loss 3173 GPC5 98 13 110754499 110778301 23802 gain 3006 ARHGEF7 99 TEX29 14 20021118 20055469 34351 gain 3205 RNASE10 100 14 20426824 20481852 55028 hom loss 3200 ECRP 101 RNASE3 14 20430810 20490129 59319 het loss 3192 ECRP 102 14 20430810 20490129 59319 het loss 3192 102 14 20430810 20490129 59319 het loss 3192 102 14 21096689 21105611 8922 het loss 3125 103 14 21096689 21105611 8922 het loss 3175 103 14 21096689 21105611 8922 het loss 3194 103 14 21096689 21105611 8922 het loss 3204 103 14 21096689 21105611 8922 het loss 3273 103 14 21120750 21125513 4763 gain 3143 104 14 21120750 21125513 4763 gain 3173 104 14 60901636 60909492 7856 het loss 3193 PRKCH 105 14 60912874 60921269 8395 het loss 3174 PRKCH 106 14 63937192 63944459 7267 gain 3205 MTHFD1 107 14 95754535 95759056 4521 het loss 3009 BDKRB2 108 14 95754535 95759056 4521 het loss 3173 BDKRB2 108 14 95754535 95759056 4521 het loss 3202 BDKRB2 108 15 66065925 66082418 16493 het loss 3010 109 15 70432627 70443017 10390 gain 3169 HEXA 110 15 75096101 75128723 32622 gain 3200 PSTPIP1 111 15 75101524 75115806 14282 gain 3132 PSTPIP1 112 15 75096101 75128723 32622 gain 3200 PSTPIP1 111 15 75105789 75115806 10017 gain 3127 PSTPIP1 113 15 75101524 75115806 14282 gain 3132 PSTPIP1 112 15 75105789 75115806 10017 gain 3199 PSTPIP1 113 15 75096101 75128723 32622 gain 3200 PSTPIP1 111 15 75105789 75115806 10017 gain 3279 PSTPIP1 113 15 75105789 75115806 10017 gain 3127 PSTPIP1 113 15 75101524 75115806 14282 gain 3132 PSTPIP1 112 15 75105789 75115806 10017 gain 3199 PSTPIP1 113 15 75096101 75128723 32622 gain 3200 PSTPIP1 111 15 75105789 75115806 10017 gain 3279 PSTPIP1 113 15 75096101 75128723 32622 gain 3200 PSTPIP1 111 15 88999998 89016848 16850 het loss 3172 114 16 6823677 6932753 109076 het loss 3126 RBFOX1 115 16 6823677 6932753 109076 het loss 3126 RBFOX1 115 16 6942078 6945539 3461 gain 3173 RBFOX1 116 16 6942078 6945539 3461 gain 3175 RBFOX1 116 16 6942078 6945539 3461 gain 3282 RBFOX1 116 16 23842653 23848772 6119 het loss 3198 PRKCB 117 16 23892842 23903495 10653 gain 3199 PRKCB 118 16 23892842 23903495 10653 gain 3199 PRKCB 118 16 23893969 23908248 14279 gain 3205 PRKCB 119 16 23893969 23908248 14279 gain 3205 PRKCB 119 16 69044235 69050151 5916 gain 3174 FUK 120 16 69044235 69050151 5916 gain 3185 FUK 120 16 69052450 69081640 29190 het loss 3197 COG4 121 FUK 16 70653499 70665447 11948 gain 3143 HPR 122 16 70653499 70665447 11948 gain 3152 HPR 122 16 70653499 70665447 11948 gain 3192 HPR 122 16 70653499 70665447 11948 gain 3200 HPR 122 16 70653499 70665447 11948 gain 3282 HPR 122 16 70653499 70665447 11948 gain 3284 HPR 122 17 69341925 70202523 860598 gain 3183 BTBD17 123 C17orf77 CD300A CD300C CD300E CD300LB CD300LD CD300LF DNAI2 GPR142 GPRC5C KIF19 MGC16275 RAB37 RPL38 TTYH2 17 75608151 75615433 7282 het loss 3144 TBC1D16 124 17 75608151 75615433 7282 het loss 3152 TBC1D16 124 17 75608151 75615433 7282 het loss 3163 TBC1D16 124 17 75608151 75611602 3451 het loss 3192 TBC1D16 125 17 75608151 75615433 7282 het loss 3200 TBC1D16 124 17 75608151 75611602 3451 het loss 3204 TBC1D16 125 17 75608151 75611602 3451 het loss 3284 TBC1D16 125 17 75608151 75611602 3451 hom loss 3009 TBC1D16 125 17 75611602 75615433 3831 hom loss 3175 TBC1D16 126 17 75608151 75615433 7282 het loss 3144 TBC1D16 124 17 75608151 75615433 7282 het loss 3152 TBC1D16 124 17 75608151 75615433 7282 het loss 3163 TBC1D16 124 17 75608151 75615433 7282 het loss 3200 TBC1D16 124 17 76241510 76267844 26334 gain 3205 RPTOR 127 17 76247305 76265683 18378 gain 3127 RPTOR 128 17 76241510 76267844 26334 gain 3205 RPTOR 127 17 76241510 76267844 26334 gain 3205 RPTOR 127 18 9985530 10125331 139801 gain 3175 129 18 12764095 12781985 17890 gain 3191 PTPN2 130 18 27026203 27029351 3148 het loss 3125 131 18 27026203 27029351 3148 het loss 3143 131 18 27026203 27029351 3148 het loss 3175 131 18 42537949 42663605 125656 gain 3125 PIAS2 132 ST8SIA5 18 46917195 46945018 27823 het loss 3161 133 18 59457622 59465699 8077 het loss 3145 SERPINB4 134 19 3270755 3291144 20389 gain 3205 135 19 46386511 46388364 1853 hom loss 3175 136 19 52496536 52501292 4756 gain 3124 137 19 55247874 55252420 4546 het loss 3163 FLJ26850 138 19 55247874 55252420 4546 het loss 3173 FLJ26850 138 19 55247874 55252420 4546 het loss 3192 FLJ26850 138 19 55247874 55252420 4546 het loss 3200 FLJ26850 138 19 55247874 55252420 4546 het loss 3280 FLJ26850 138 19 55247874 55252420 4546 het loss 3163 FLJ26850 138 19 55247874 55252420 4546 het loss 3173 FLJ26850 138 19 55247874 55252420 4546 het loss 3192 FLJ26850 138 19 55250187 55252420 2233 het loss 3194 FLJ26850 139 19 55247874 55252420 4546 het loss 3200 FLJ26850 138 19 55247874 55252420 4546 het loss 3280 FLJ26850 138 19 55250187 55252420 2233 hom loss 3175 FLJ26850 139 19 55250187 55252420 2233 hom loss 3202 FLJ26850 139 19 56964168 57308449 344281 gain 3155 FPR2 140 FPR3 ZNF350 ZNF432 ZNF577 ZNF613 ZNF614 ZNF615 ZNF649 ZNF841 19 56964168 57308449 344281 gain 3157 FPR2 140 FPR3 ZNF350 ZNF432 ZNF577 ZNF613 ZNF614 ZNF615 ZNF649 ZNF841 19 59013780 59023850 10070 het loss 3117 NLRP12 141 19 59249279 59251831 2552 hom loss 3160 VSTM1 142 19 59249279 59251831 2552 hom loss 3164 VSTM1 142 19 59250742 59251831 1089 hom loss 3117 VSTM1 143 19 59249279 59251831 2552 hom loss 3160 VSTM1 142 19 59249279 59251831 2552 hom loss 3164 VSTM1 142 19 59250742 59251831 1089 hom loss 3277 VSTM1 143 20 17844577 17954650 110073 gain 3166 MGME1 144 OVOL2 SNORD17 SNX5 20 42706680 42711434 4754 het loss 3125 ADA 145 21 15234620 15312960 78340 gain 3009 NRIP1 146 21 29643302 29647950 4648 het loss 3202 BACH1 147 21 44634707 44666832 32125 gain 3200 TRPM2 148 21 44634707 44641658 6951 gain 3205 TRPM2 149 21 44634707 44671482 36775 gain 3279 TRPM2 150 21 44637544 44669596 32052 gain 3127 TRPM2 151 21 44637544 44657372 19828 gain 3185 TRPM2 152 21 44634707 44666832 32125 gain 3200 TRPM2 148 21 44634707 44641658 6951 gain 3205 TRPM2 149 21 44634707 44671482 36775 gain 3279 TRPM2 150 21 44637544 44669596 32052 gain 3127 TRPM2 151 21 44637544 44657372 19828 gain 3185 TRPM2 152 21 44634707 44666832 32125 gain 3200 TRPM2 148 21 44634707 44671482 36775 gain 3279 TRPM2 150 21 44643974 44657372 13398 het loss 3161 TRPM2 153 21 44637544 44669596 32052 gain 3127 TRPM2 151 21 44637544 44657372 19828 gain 3185 TRPM2 152 21 44634707 44666832 32125 gain 3200 TRPM2 148 21 44643974 44657372 13398 gain 3205 TRPM2 153 21 44634707 44671482 36775 gain 3279 TRPM2 150 21 44637544 44669596 32052 gain 3127 TRPM2 151 21 44634707 44666832 32125 gain 3200 TRPM2 148 21 44634707 44671482 36775 gain 3279 TRPM2 150 21 44637544 44669596 32052 gain 3127 TRPM2 151 21 44634707 44666832 32125 gain 3200 TRPM2 148 21 44660199 44681194 20995 gain 3205 TRPM2 154 21 44634707 44671482 36775 gain 3279 TRPM2 150 21 44637544 44669596 32052 gain 3127 TRPM2 151 21 44660199 44681194 20995 gain 3205 TRPM2 154 21 44634707 44671482 36775 gain 3279 TRPM2 150 21 44660199 44681194 20995 gain 3205 TRPM2 154 21 44634707 44671482 36775 gain 3279 TRPM2 150 21 44660199 44681194 20995 gain 3205 TRPM2 154 21 45348895 45354820 5925 het loss 3179 ADARB1 155 22 37689058 37715385 26327 gain 3169 APOBEC3A 156 APOBEC3A B APOBEC3B 22 39257585 39261621 4036 het loss 3005 MKL1 157 22 40642402 40655210 12808 gain 3205 TNFRSF13C 158 22 40655820 40673250 17430 gain 3185 159 22 40655820 40675788 19968 gain 3205 160 22 40659633 40671866 12233 gain 3127 161 22 40655820 40673250 17430 gain 3185 159 22 40655820 40675788 19968 gain 3205 160 22 40659633 40671866 12233 gain 3127 CENPM 161 22 40655820 40673250 17430 gain 3185 CENPM 159 22 40663050 40668079 5029 gain 3190 CENPM 162 22 40663050 40668079 5029 gain 3202 CENPM 162 22 40655820 40675788 19968 gain 3205 CENPM 160 22 40659633 40671866 12233 gain 3127 CENPM 161 22 40655820 40673250 17430 gain 3185 CENPM 159 22 40655820 40675788 19968 gain 3205 CENPM 160 22 40655820 40673250 17430 gain 3185 CENPM 159 22 40655820 40675788 19968 gain 3205 CENPM 160 22 40655820 40675788 19968 gain 3205 160 23 232907 244684 11777 het loss 3007 PPP2R3B 163 23 7585301 7830994 245693 gain 3172 164 23 7585301 7830994 245693 gain 3172 VCX 164 23 7769323 7779354 10031 het loss 3132 165 23 6465033 8093113 1628080 het loss 3171 166 23 7769323 7779354 10031 het loss 3204 165 23 7585301 7830994 245693 gain 3172 164 23 7585301 7830994 245693 gain 3172 164 23 6465033 8093113 1628080 het loss 3171 MIR651 166 PNPLA4 23 7585301 7830994 245693 gain 3172 PNPLA4 164 23 48358646 48408854 50208 het loss 3009 167 23 64710574 64725828 15254 gain 3125 168 23 73083877 73086192 2315 hom loss 3193 JPX 169 23 73083877 73086192 2315 hom loss 3200 JPX 169 23 122337025 122340879 3854 hom loss 3125 GRIA3 170 23 148452844 148461889 9045 het loss 3163 171 23 148452844 148461889 9045 het loss 3205 171 23 148452844 148461889 9045 hom loss 3144 171 23 148452844 148461889 9045 hom loss 3193 171 23 149901706 149904265 2559 gain 3117 HMGB3 172 23 149901706 149904265 2559 gain 3118 HMGB3 172

Table 1 lists all CNVs of interest, obtained as described in the text, with the exception that, for each entry, the original CNV start and stop positions are noted, along with original CNV size, type (heterozygous loss, homozygous loss or gain), Case ID and gene annotation (for the CNV-subregion NOT original CNV). The final column contains SEQ ID numbers. Standard chromosomal numbering used by those skilled in the art is used in Table 1 for the autosomal chromosomes (1-22) but, for convenience with analysis methods, chromosome X is designated as chromosome 23 herein. All coordinates are based on hg18.

TABLE 2 CNV-subregions of interest in this study CNV CNV Sub- CNV CNV Sub- PML RefSeq region Subregion Subregion region CNV Case Gene Exon NVE PML No Chr Start Stop Size Type ID Symbol overlap cases cases FET OR (SRN) 1 1086119 1135772 49653 het loss 3009 MIR200A Y 0 1 0.005115965 39.43 1 MIR200B M1R429 TNFRSF18 TTLL10 1 9634094 9635206 1112 hom loss 3009 PIK3CD Y 0 1 0.005115965 39.43 2 1 12018512 12032581 14069 gain 3205 N 0 1 0.005115965 39.43 3 1 19593401 19602807 9406 het loss 3203 CAPZB N 0 1 0.005115965 39.43 4 1 21698753 21700243 1490 het loss 3161 N 0 1 0.005115965 39.43 5 1 24364786 24391166 26380 gain 3199 IFNLR1 Y 0 1 0.005115965 39.43 6 1 28666669 28737671 71002 gain 3161 PHACTR4 Y 0 1 0.005115965 39.43 7 RCC1 SNHG3 1 49372054 49380088 8034 het loss 3145 AGBL4 N 0 1 0.005115965 39.43 8 1 153816159 153827698 11539 het loss 3168 N 0 1 0.005115965 39.43 9 1 205607255 205610341 3086 gain 3007 N 0 1 0.005115965 39.43 10 1 215760485 215762451 1966 het loss 3117 GPATCH2 N 0 1 0.005115965 39.43 11 1 215866737 215869900 3163 het loss 3151 GPATCH2 N 0 1 0.005115965 39.43 12 2 10352668 10356083 3415 het loss 3007 N 0 1 0.005115965 39.43 13 2 24457024 24462631 5607 hom loss 3204 N 0 1 0.005115965 39.43 14 2 38468717 38471950 3233 het loss 3175 N 0 1 0.005115965 39.43 15 2 38516138 38524237 8099 het loss 3151 N 0 1 0.005115965 39.43 16 2 38726517 38731845 5328 het loss 3159 N 0 1 0.005115965 39.43 17 2 40620890 40624089 3199 het loss 3202 N 0 1 0.005115965 39.43 18 2 46631006 46643501 12495 gain 3145 RHOQ N 0 1 0.005115965 39.43 19 2 55764753 55771586 6833 gain 3143 PNPT1 Y 1 3 0.001318303 40.7 20 2 55764753 55771586 6833 gain 3193 PNPT1 Y 1 3 0.001318303 40.7 21 2 55764753 55771586 6833 gain 3282 PNPT1 Y 1 3 0.001318303 40.7 22 2 55771587 55772965 1378 gain 3143 PNPT1 N 2 3 0.003126725 20.33 23 2 55771587 55772965 1378 gain 3193 PNPT1 N 2 3 0.003126725 20.33 24 2 55771587 55772965 1378 gain 3282 PNPT1 N 2 3 0.003126725 20.33 25 2 55772966 55790559 17593 gain 3143 PNPT1 Y 1 3 0.001318303 40.7 26 2 55772966 55790559 17593 gain 3193 PNPT1 Y 1 3 0.001318303 40.7 27 2 55772966 55790559 17593 gain 3282 PNPT1 Y 1 3 0.001318303 40.7 28 2 71190677 71191310 633 het loss 3175 MCEE Y 0 1 0.005115965 39.43 29 2 71191311 71198107 6796 het loss 3175 MCEE N 1 2 0.014314826 26.77 30 2 71191311 71198107 6796 het loss 3204 MCEE N 1 2 0.014314826 26.77 31 2 71198108 71200120 2012 het loss 3143 MCEE N 2 5 3.02E−05 34.83 32 2 71198108 71200120 2012 het loss 3175 MCEE N 2 5 3.02E−05 34.83 33 2 71198108 71200120 2012 het loss 3193 MCEE N 2 5 3.02E−05 34.83 34 2 71198108 71200120 2012 het loss 3200 MCEE N 2 5 3.02E−05 34.83 35 2 71198108 71200120 2012 het loss 3204 MCEE N 2 5 3.02E−05 34.83 36 2 74827730 74913493 85763 gain 3118 HK2 Y 0 1 0.005115965 39.43 37 2 105418748 105435274 16526 het loss 3193 FHL2 Y 0 1 0.005115965 39.43 38 2 110182348 110210249 27901 gain 3174 MALL Y 2 1 0.198831257 6.6 39 MIR4267 MIR4436B1 MIR4436B2 2 127823042 127828410 5368 het loss 3273 N 0 1 0.005115965 39.43 40 2 134911636 134914254 2618 het loss 3273 MGAT5 N 0 1 0.005115965 39.43 41 2 203005216 203019933 14717 het loss 3009 BMPR2 N 2 2 0.02731135 13.37 42 2 203005216 203019933 14717 het loss 3192 BMPR2 N 2 2 0.02731135 13.37 43 2 203005216 203019933 14717 hom loss 3152 BMPR2 N 0 1 0.005115965 39.43 44 2 230212897 230216339 3442 het loss 3154 DNER N 0 1 0.005115965 39.43 45 3 122979920 122994402 14482 gain 3202 IQCB1 Y 0 1 0.005115965 39.43 46 4 26565071 26566345 1274 het loss 3010 STIM2 N 85 5 0.671895631 0.75 47 4 26565071 26566345 1274 het loss 3125 STIM2 N 85 5 0.671895631 0.75 48 4 26565071 26566345 1274 het loss 3168 STIM2 N 85 5 0.671895631 0.75 49 4 26565071 26566345 1274 het loss 3282 STIM2 N 85 5 0.671895631 0.75 50 4 26565071 26566345 1274 het loss 3284 STIM2 N 85 5 0.671895631 0.75 51 4 26565071 26566345 1274 hom loss 3273 STIM2 N 1 1 0.13732578 13.21 52 4 54838623 54873909 35286 gain 3153 PDGFRA Y 0 1 0.005115965 39.43 53 4 90791460 90843887 52427 gain 3168 N 0 1 0.005115965 39.43 54 4 90800863 90808258 7395 het loss 3009 N 0 2 0.005115965 66.59 55 4 90800863 90808258 7395 het loss 3284 N 0 2 0.005115965 66.59 56 5 45331278 45785151 453873 gain 3157 HCN1 Y 0 1 0.005115965 39.43 57 5 49771219 49774457 3238 gain 3273 EMB Y 0 1 0.005115965 39.43 58 5 66619415 66636116 16701 gain 3010 N 0 1 0.005115965 39.43 59 5 78480194 78497296 17102 gain 3205 N 0 1 0.005115965 39.43 60 5 78497296 78500551 3255 gain 3132 N 0 2 0.005115965 66.59 61 5 78497296 78500551 3255 gain 3185 N 0 2 0.005115965 66.59 62 5 78500552 78521408 20856 gain 3132 N 0 3 2.49E−05 94.48 63 5 78500552 78521408 20856 gain 3185 N 0 3 2.49E−05 94.48 64 5 78500552 78521408 20856 gain 3205 N 0 3 2.49E−05 94.48 65 5 78521409 78526637 5228 gain 3132 N 0 2 0.005115965 66.59 66 5 78521409 78526637 5228 gain 3205 N 0 2 0.005115965 66.59 67 5 78526638 78531091 4453 gain 3132 N 0 1 0.005115965 39.43 68 5 83490494 83495169 4675 het loss 3204 EDIL3 N 0 1 0.005115965 39.43 69 5 133372071 133379727 7656 hom loss 3153 N 0 1 0.005115965 39.43 70 5 137836466 137843309 6843 hom loss 3279 N 1 1 0.13732578 13.21 71 5 150159466 150161037 1571 het loss 3117 N 15 4 0.040487703 3.62 72 5 150159466 150161037 1571 het loss 3180 N 15 4 0.040487703 3.62 73 5 150159466 150161037 1571 het loss 3199 N 15 4 0.040487703 3.62 74 5 150159466 150161037 1571 het loss 3278 N 15 4 0.040487703 3.62 75 5 150161038 150181399 20361 het loss 3117 N 14 4 0.033744017 3.88 76 5 150161038 150181399 20361 het loss 3180 N 14 4 0.033744017 3.88 77 5 150161038 150181399 20361 het loss 3199 N 14 4 0.033744017 3.88 78 5 150161038 150181399 20361 het loss 3278 N 14 4 0.033744017 3.88 79 5 150181400 150185189 3789 het loss 3117 N 13 4 0.027710312 4.18 80 5 150181400 150185189 3789 het loss 3180 N 13 4 0.027710312 4.18 81 5 150181400 150185189 3789 het loss 3199 N 13 4 0.027710312 4.18 82 5 150181400 150185189 3789 het loss 3278 N 13 4 0.027710312 4.18 83 5 150185190 150191626 6436 hom loss 3009 N 6 7 8.59E−06 16.65 84 5 150185190 150191626 6436 hom loss 3143 N 6 7 8.59E−06 16.65 85 5 150185190 150191626 6436 hom loss 3152 N 6 7 8.59E−06 16.65 86 5 150185190 150191626 6436 hom loss 3154 N 6 7 8.59E−06 16.65 87 5 150185190 150191626 6436 hom loss 3193 N 6 7 8.59E−06 16.65 88 5 150185190 150191626 6436 hom loss 3196 N 6 7 8.59E−06 16.65 89 5 150185190 150191626 6436 hom loss 3281 N 6 7 8.59E−06 16.65 90 5 150191627 150201145 9518 hom loss 3009 N 6 7 8.59E−06 16.65 91 5 150191627 150201145 9518 hom loss 3143 N 6 7 8.59E−06 16.65 92 5 150191627 150201145 9518 hom loss 3152 N 6 7 8.59E−06 16.65 93 5 150191627 150201145 9518 hom loss 3154 N 6 7 8.59E−06 16.65 94 5 150191627 150201145 9518 hom loss 3193 N 6 7 8.59E−06 16.65 95 5 150191627 150201145 9518 hom loss 3196 N 6 7 8.59E−06 16.65 96 5 150191627 150201145 9518 hom loss 3281 N 6 7 8.59E−06 16.65 97 5 150201146 150202601 1455 hom loss 3152 N 1 3 0.001318303 40.7 98 5 150201146 150202601 1455 hom loss 3154 N 1 3 0.001318303 40.7 99 5 150201146 150202601 1455 hom loss 3193 N 1 3 0.001318303 40.7 100 5 150202602 150204134 1532 het loss 3132 N 51 8 0.062987683 2.17 101 5 150202602 150204134 1532 het loss 3180 N 51 8 0.062987683 2.17 102 5 150202602 150204134 1532 het loss 3196 N 51 8 0.062987683 2.17 103 5 150202602 150204134 1532 het loss 3273 N 51 8 0.062987683 2.17 104 5 150202602 150204134 1532 het loss 3277 N 51 8 0.062987683 2.17 105 5 150202602 150204134 1532 het loss 3278 N 51 8 0.062987683 2.17 106 5 150202602 150204134 1532 het loss 3280 N 51 8 0.062987683 2.17 107 5 150202602 150204134 1532 het loss 3282 N 51 8 0.062987683 2.17 108 5 179590681 179626660 35979 het loss 3172 MAPK9 Y 0 1 0.005115965 39.43 109 6 2882577 2947403 64826 het loss 3196 DKFZP686I15217 Y 0 1 0.005115965 39.43 110 NQO2 SERPINB6 6 2964646 2966011 1365 het loss 3193 HTATSF1P2 Y 0 1 0.005115965 39.43 111 NQO2 6 51766024 51773250 7226 het loss 3167 PKHD1 N 0 1 0.005115965 39.43 112 6 51952217 51953475 1258 gain 3127 PKHD1 N 0 1 0.005115965 39.43 113 6 51953476 51965723 12247 gain 3127 PKHD1 N 0 2 0.005115965 66.59 114 6 51953476 51965723 12247 gain 3205 PKHD1 N 0 2 0.005115965 66.59 115 6 51965724 51969378 3654 gain 3127 PKHD1 N 0 1 0.005115965 39.43 116 6 74396294 74398409 2115 het loss 3009 SLC17A5 N 0 2 0.005115965 66.59 117 6 74396294 74398409 2115 het loss 3160 SLC17A5 N 0 2 0.005115965 66.59 118 6 74398410 74404837 6427 het loss 3009 SLC17A5 Y 0 1 0.005115965 39.43 119 6 86416979 86431527 14548 het loss 3197 N 0 1 0.005115965 39.43 120 6 91131823 91135670 3847 het loss 3171 N 0 1 0.005115965 39.43 121 6 107882367 107890605 8238 het loss 3201 PDSS2 Y 0 1 0.005115965 39.43 122 6 166418511 166422386 3875 het loss 3125 N 11 10 3.49E−07 13.49 123 6 166418511 166422386 3875 het loss 3163 N 11 10 3.49E−07 13.49 124 6 166418511 166422386 3875 het loss 3192 N 11 10 3.49E−07 13.49 125 6 166418511 166422386 3875 het loss 3193 N 11 10 3.49E−07 13.49 126 6 166418511 166422386 3875 het loss 3194 N 11 10 3.49E−07 13.49 127 6 166418511 166422386 3875 het loss 3200 N 11 10 3.49E−07 13.49 128 6 166418511 166422386 3875 het loss 3205 N 11 10 3.49E−07 13.49 129 6 166418511 166422386 3875 het loss 3280 N 11 10 3.49E−07 13.49 130 6 166418511 166422386 3875 het loss 3281 N 11 10 3.49E−07 13.49 131 6 166418511 166422386 3875 het loss 3284 N 11 10 3.49E−07 13.49 132 6 166418511 166422386 3875 hom loss 3009 N 0 3 2.49E−05 94.48 133 6 166418511 166422386 3875 hom loss 3152 N 0 3 2.49E−05 94.48 134 6 166418511 166422386 3875 hom loss 3175 N 0 3 2.49E−05 94.48 135 7 65741238 65768682 27444 gain 3152 KCTD7 Y 0 2 0.005115965 66.59 136 7 65741238 65768682 27444 gain 3202 KCTD7 Y 0 2 0.005115965 66.59 137 7 157174966 157177843 2877 het loss 3009 PTPRN2 N 0 1 0.005115965 39.43 138 7 157425841 157496238 70397 gain 3189 PTPRN2 N 1 1 0.13732578 13.21 139 7 158000082 158007892 7810 het loss 3279 PTPRN2 N 1 1 0.13732578 13.21 140 7 158007893 158010672 2779 het loss 3279 PTPRN2 N 5 1 0.358539546 2.63 141 7 158010673 158024569 13896 het loss 3279 MIR595 Y 1 1 0.13732578 13.21 142 PTPRN2 8 23103186 23125443 22257 het loss 3140 TNFRSF10A Y 0 1 0.005115965 39.43 143 8 39914488 39919594 5106 het loss 3126 IDO2 N 0 1 0.005115965 39.43 144 8 79905654 79910286 4632 het loss 3159 N 0 1 0.005115965 39.43 145 8 99790200 99799839 9639 het loss 3006 STK3 N 0 1 0.005115965 39.43 146 8 102049360 102064431 15071 het loss 3173 N 0 3 2.49E−05 94.48 147 8 102049360 102064431 15071 het loss 3175 N 0 3 2.49E−05 94.48 148 8 102049360 102064431 15071 het loss 3282 N 0 3 2.49E−05 94.48 149 9 571398 580721 9323 het loss 3006 KANK1 N 2 1 0.198831257 6.6 150 9 580722 584647 3925 het loss 3006 KANK1 N 3 3 0.005933668 13.54 151 9 580722 584647 3925 het loss 3200 KANK1 N 3 3 0.005933668 13.54 152 9 580722 584647 3925 het loss 3282 KANK1 N 3 3 0.005933668 13.54 153 9 584648 598488 13840 het loss 3200 KANK1 N 2 2 0.02731135 13.37 154 9 584648 598488 13840 het loss 3282 KANK1 N 2 2 0.02731135 13.37 155 9 634039 637589 3550 het loss 3273 KANK1 N 0 2 0.005115965 66.59 156 9 634039 637589 3550 het loss 3282 KANK1 N 0 2 0.005115965 66.59 157 9 74050088 74059447 9359 het loss 3165 GDA Y 0 1 0.005115965 39.43 158 9 93140394 93447826 307432 gain 3198 AUH Y 0 1 0.005115965 39.43 159 MIR3163 MIR3910-1 MIR3910-2 NFIL3 9 118564159 118575633 11474 gain 3193 ASTN2 N 0 1 0.005115965 39.43 160 9 118657526 118664593 7067 het loss 3144 ASTN2 N 0 1 0.005115965 39.43 161 9 119220847 119233078 12231 gain 3005 N 0 1 0.005115965 39.43 162 10 899657 1071401 171744 gain 3161 GTPBP4 Y 0 1 0.005115965 39.43 163 IDI2 IDI2-AS1 LARP4B 10 76217585 76411591 194006 gain 3179 KAT6B Y 0 1 0.005115965 39.43 164 10 116000069 116004388 4319 gain 3010 VWA2 Y 0 1 0.005115965 39.43 165 11 14677012 14689025 12013 het loss 3199 PDE3B N 0 1 0.005115965 39.43 166 11 34608313 34615878 7565 het loss 3117 EHF Y 0 1 0.005115965 39.43 167 11 62382087 62398462 16375 het loss 3205 SLC3A2 Y 0 1 0.005115965 39.43 168 11 76631014 76643625 12611 het loss 3193 GDPD4 Y 0 1 0.005115965 39.43 169 12 11616557 12114030 497473 het loss 3126 ETV6 Y 0 1 0.005115965 39.43 170 12 12438904 12778142 339238 het loss 3126 APOLD1 Y 0 1 0.005115965 39.43 171 CDKN1B CREBL2 DUSP16 GPR19 LOH12CR1 12 12968705 12971310 2605 gain 3127 N 0 1 0.005115965 39.43 172 12 91845527 92201342 355815 het loss 3126 EEA1 Y 0 1 0.005115965 39.43 173 LOC643339 12 92215898 92567120 351222 het loss 3126 LOC643339 Y 0 1 0.005115965 39.43 174 MRPL42 NUDT4 NUDT4P1 SOCS2 SOCS2-AS1 UBE2N 12 92568362 93307172 738810 het loss 3126 CCDC41 Y 0 1 0.005115965 39.43 175 CRADD PLXNC1 12 111061085 111064486 3401 het loss 3004 TRAFD1 Y 0 1 0.005115965 39.43 176 13 40939924 41026908 86984 gain 3140 RGCC Y 0 1 0.005115965 39.43 177 13 75006025 75016304 10279 gain 3009 COMMD6 Y 0 2 0.005115965 66.59 178 13 75006025 75016304 10279 gain 3152 COMMD6 Y 0 2 0.005115965 66.59 179 13 91811087 91814369 3282 het loss 3143 GPC5 N 1 1 0.13732578 13.21 180 13 91811087 91811118 31 hom loss 3173 GPC5 N 0 1 0.005115965 39.43 181 13 110754499 110778301 23802 gain 3006 ARHGEF7 Y 0 1 0.005115965 39.43 182 TEX29 14 20021118 20055469 34351 gain 3205 RNASE10 Y 0 1 0.005115965 39.43 183 14 20426824 20481852 55028 hom loss 3200 ECRP Y 0 1 0.005115965 39.43 184 RNASE3 14 20430810 20458350 27540 het loss 3192 ECRP Y 3 1 0.256004559 4.39 185 14 20458351 20481852 23501 het loss 3192 N 4 1 0.309147091 3.29 186 14 20481853 20490129 8276 het loss 3192 N 1 1 0.13732578 13.21 187 14 21096689 21105611 8922 het loss 3125 N 0 5 1.16E−07 152.56 188 14 21096689 21105611 8922 het loss 3175 N 0 5 1.16E−07 152.56 189 14 21096689 21105611 8922 het loss 3194 N 0 5 1.16E−07 152.56 190 14 21096689 21105611 8922 het loss 3204 N 0 5 1.16E−07 152.56 191 14 21096689 21105611 8922 het loss 3273 N 0 5 1.16E−07 152.56 192 14 21120750 21125513 4763 gain 3143 N 1 2 0.014314826 26.77 193 14 21120750 21125513 4763 gain 3173 N 1 2 0.014314826 26.77 194 14 60901636 60909492 7856 het loss 3193 PRKCH N 0 1 0.005115965 39.43 195 14 60912874 60921269 8395 het loss 3174 PRKCH N 0 1 0.005115965 39.43 196 14 63937192 63944459 7267 gain 3205 MTHFD1 Y 0 1 0.005115965 39.43 197 14 95754535 95759056 4521 het loss 3009 BDKRB2 N 0 3 2.49E−05 94.48 198 14 95754535 95759056 4521 het loss 3173 BDKRB2 N 0 3 2.49E−05 94.48 199 14 95754535 95759056 4521 het loss 3202 BDKRB2 N 0 3 2.49E−05 94.48 200 15 66065925 66082418 16493 het loss 3010 N 0 1 0.005115965 39.43 201 15 70432627 70443017 10390 gain 3169 HEXA Y 0 1 0.005115965 39.43 202 15 75096101 75101523 5422 gain 3200 PSTPIP1 Y 0 1 0.005115965 39.43 203 15 75101524 75105788 4264 gain 3132 PSTPIP1 Y 0 2 0.005115965 66.59 204 15 75101524 75105788 4264 gain 3200 PSTPIP1 Y 0 2 0.005115965 66.59 205 15 75105789 75109086 3297 gain 3127 PSTPIP1 Y 0 5 1.16E−07 152.56 206 15 75105789 75109086 3297 gain 3132 PSTPIP1 Y 0 5 1.16E−07 152.56 207 15 75105789 75109086 3297 gain 3199 PSTPIP1 Y 0 5 1.16E−07 152.56 208 15 75105789 75109086 3297 gain 3200 PSTPIP1 Y 0 5 1.16E−07 152.56 209 15 75105789 75109086 3297 gain 3279 PSTPIP1 Y 0 5 1.16E−07 152.56 210 15 75109087 75115806 6719 gain 3127 PSTPIP1 Y 1 5 9.14E−06 69.72 211 15 75109087 75115806 6719 gain 3132 PSTPIP1 Y 1 5 9.14E−06 69.72 212 15 75109087 75115806 6719 gain 3199 PSTPIP1 Y 1 5 9.14E−06 69.72 213 15 75109087 75115806 6719 gain 3200 PSTPIP1 Y 1 5 9.14E−06 69.72 214 15 75109087 75115806 6719 gain 3279 PSTPIP1 Y 1 5 9.14E−06 69.72 215 15 75115807 75117798 1991 gain 3200 PSTPIP1 Y 1 1 0.13732578 13.21 216 15 88999998 89016848 16850 het loss 3172 N 0 1 0.005115965 39.43 217 16 6823677 6884976 61299 het loss 3126 RBFOX1 N 0 1 0.005115965 39.43 218 16 6886815 6896330 9515 het loss 3126 RBFOX1 N 0 1 0.005115965 39.43 219 16 6942078 6945539 3461 gain 3173 RBFOX1 N 1 3 0.001318303 40.7 220 16 6942078 6945539 3461 gain 3175 RBFOX1 N 1 3 0.001318303 40.7 221 16 6942078 6945539 3461 gain 3282 RBFOX1 N 1 3 0.001318303 40.7 222 16 23844022 23848772 4750 het loss 3198 PRKCB N 7 1 0.447101793 1.88 223 16 23892842 23893968 1126 gain 3199 PRKCB N 0 1 0.005115965 39.43 224 16 23893969 23903495 9526 gain 3199 PRKCB N 0 2 0.005115965 66.59 225 16 23893969 23903495 9526 gain 3205 PRKCB N 0 2 0.005115965 66.59 226 16 23903496 23908248 4752 gain 3205 PRKCB Y 0 1 0.005115965 39.43 227 16 69047888 69050151 2263 gain 3174 FUK N 0 2 0.005115965 66.59 228 16 69047888 69050151 2263 gain 3185 FUK N 0 2 0.005115965 66.59 229 16 69052450 69081640 29190 het loss 3197 COG4 Y 0 1 0.005115965 39.43 230 FUK 16 70653499 70665447 11948 gain 3143 HPR Y 0 6 1.16E−07 182.82 231 16 70653499 70665447 11948 gain 3152 HPR Y 0 6 1.16E−07 182.82 232 16 70653499 70665447 11948 gain 3192 HPR Y 0 6 1.16E−07 182.82 233 16 70653499 70665447 11948 gain 3200 HPR Y 0 6 1.16E−07 182.82 234 16 70653499 70665447 11948 gain 3282 HPR Y 0 6 1.16E−07 182.82 235 16 70653499 70665447 11948 gain 3284 HPR Y 0 6 1.16E−07 182.82 236 17 69341925 70202523 860598 gain 3183 BTBD17 Y 1 1 0.13732578 13.21 237 C17orf77 CD300A CD300C CD300E CD300LB CD300LD CD300LF DNAI2 GPR142 GPRC5C KIF19 MGC16275 RAB37 RPL38 TTYH2 17 75608151 75611602 3451 het loss 3144 TBC1D16 N 1 7 5.37E−08 100.4 238 17 75608151 75611602 3451 het loss 3152 TBC1D16 N 1 7 5.37E−08 100.4 239 17 75608151 75611602 3451 het loss 3163 TBC1D16 N 1 7 5.37E−08 100.4 240 17 75608151 75611602 3451 het loss 3192 TBC1D16 N 1 7 5.37E−08 100.4 241 17 75608151 75611602 3451 het loss 3200 TBC1D16 N 1 7 5.37E−08 100.4 242 17 75608151 75611602 3451 het loss 3204 TBC1D16 N 1 7 5.37E−08 100.4 243 17 75608151 75611602 3451 het loss 3284 TBC1D16 N 1 7 5.37E−08 100.4 244 17 75608151 75611602 3451 hom loss 3009 TBC1D16 N 0 1 0.005115965 39.43 245 17 75611602 75615433 3831 hom loss 3175 TBC1D16 N 0 1 0.005115965 39.43 246 17 75611603 75615433 3830 het loss 3144 TBC1D16 N 1 4 0.000112689 55.01 247 17 75611603 75615433 3830 het loss 3152 TBC1D16 N 1 4 0.000112689 55.01 248 17 75611603 75615433 3830 het loss 3163 TBC1D16 N 1 4 0.000112689 55.01 249 17 75611603 75615433 3830 het loss 3200 TBC1D16 N 1 4 0.000112689 55.01 250 17 76241510 76247304 5794 gain 3205 RPTOR N 0 1 0.005115965 39.43 251 17 76247305 76265683 18378 gain 3127 RPTOR N 0 2 0.005115965 66.59 252 17 76247305 76265683 18378 gain 3205 RPTOR N 0 2 0.005115965 66.59 253 17 76265684 76267844 2160 gain 3205 RPTOR N 0 1 0.005115965 39.43 254 18 9985530 10125331 139801 gain 3175 N 0 1 0.005115965 39.43 255 18 12764095 12781985 17890 gain 3191 PTPN2 Y 0 1 0.005115965 39.43 256 18 27026203 27029351 3148 het loss 3125 N 0 3 2.49E−05 94.48 257 18 27026203 27029351 3148 het loss 3143 N 0 3 2.49E−05 94.48 258 18 27026203 27029351 3148 het loss 3175 N 0 3 2.49E−05 94.48 259 18 42537949 42663605 125656 gain 3125 PIA2 Y 0 1 0.005115965 39.43 260 ST8SIA5 18 46917195 46945018 27823 het loss 3161 N 0 1 0.005115965 39.43 261 18 59457622 59465699 8077 het loss 3145 SERPINB4 Y 0 1 0.005115965 39.43 262 19 3270755 3291144 20389 gain 3205 N 0 1 0.005115965 39.43 263 19 46386511 46388364 1853 het loss 3175 N 0 1 0.005115965 39.43 264 19 52496536 52501292 4756 gain 3124 N 0 1 0.005115965 39.43 265 19 55247874 55250186 2312 het loss 3163 FLJ26850 N 4 5 0.000161709 17.38 266 19 55247874 55250186 2312 het loss 3173 FLJ26850 N 4 5 0.000161709 17.38 267 19 55247874 55250186 2312 het loss 3192 FLJ26850 N 4 5 0.000161709 17.38 268 19 55247874 55250186 2312 het loss 3200 FLJ26850 N 4 5 0.000161709 17.38 269 19 55247874 55250186 2312 het loss 3280 FLJ26850 N 4 5 0.000161709 17.38 270 19 55250187 55252420 2233 het loss 3163 FLJ26850 N 4 6 1.80E−05 21.15 271 19 55250187 55252420 2233 het loss 3173 FLJ26850 N 4 6 1.80E−05 21.15 272 19 55250187 55252420 2233 het loss 3192 FLJ26850 N 4 6 1.80E−05 21.15 273 19 55250187 55252420 2233 het loss 3194 FLJ26850 N 4 6 1.80E−05 21.15 274 19 55250187 55252420 2233 het loss 3200 FLJ26850 N 4 6 1.80E−05 21.15 275 19 55250187 55252420 2233 het loss 3280 FLJ26850 N 4 6 1.80E−05 21.15 276 19 55250187 55252420 2233 hom loss 3175 FLJ26850 N 0 2 0.005115965 66.59 277 19 55250187 55252420 2233 hom loss 3202 FLJ26850 N 0 2 0.005115965 66.59 278 19 56964168 57308449 344281 gain 3155 FPR2 Y 3 2 0.043434433 8.91 279 FPR3 ZNF350 ZNF432 ZNF577 ZNF613 ZNF614 ZNF615 ZNF649 ZNF841 19 56964168 57308449 344281 gain 3157 FPR2 Y 3 2 0.043434433 8.91 280 FPR3 ZNF350 ZNF432 ZNF577 ZNF613 ZNF614 ZNF615 ZNF649 ZNF841 19 59016855 59023850 6995 het loss 3117 NLRP12 Y 0 1 0.005115965 39.43 281 19 59249279 59250741 1462 hom loss 3160 VSTM1 N 37 2 1 0.7 282 19 59249279 59250741 1462 hom loss 3164 VSTM1 N 37 2 1 0.7 283 19 59250742 59251831 1089 hom loss 3117 VSTM1 N 38 4 0.533838399 1.39 284 19 59250742 59251831 1089 hom loss 3160 VSTM1 N 38 4 0.533838399 1.39 285 19 59250742 59251831 1089 hom loss 3164 VSTM1 N 38 4 0.533838399 1.39 286 19 59250742 59251831 1089 hom loss 3277 VSTM1 N 38 4 0.533838399 1.39 287 20 17844577 17954650 110073 gain 3166 MGME1 Y 0 1 0.005115965 39.43 288 OVOL2 SNORD17 SNX5 20 42706680 42711434 4754 het loss 3125 ADA N 0 1 0.005115965 39.43 289 21 15237071 15312960 75889 gain 3009 NR1P1 Y 0 1 0.005115965 39.43 290 21 29643302 29647950 4648 het loss 3202 BACH1 Y 0 1 0.005115965 39.43 291 21 44634707 44637543 2836 gain 3200 TRPM2 Y 1 3 0.001318303 40.7 292 21 44634707 44637543 2836 gain 3205 TRPM2 Y 1 3 0.001318303 40.7 293 21 44634707 44637543 2836 gain 3279 TRPM2 Y 1 3 0.001318303 40.7 294 21 44637544 44641658 4114 gain 3127 TRPM2 Y 1 5 9.14E−06 69.72 295 21 44637544 44641658 4114 gain 3185 TRPM2 Y 1 5 9.14E−06 69.72 296 21 44637544 44641658 4114 gain 3200 TRPM2 Y 1 5 9.14E−06 69.72 297 21 44637544 44641658 4114 gain 3205 TRPM2 Y 1 5 9.14E−06 69.72 298 21 44637544 44641658 4114 gain 3279 TRPM2 Y 1 5 9.14E−06 69.72 299 21 44641659 44643973 2314 gain 3127 TRPM2 Y 1 4 0.000112689 55.01 300 21 44641659 44643973 2314 gain 3185 TRPM2 Y 1 4 0.000112689 55.01 301 21 44641659 44643973 2314 gain 3200 TRPM2 Y 1 4 0.000112689 55.01 302 21 44641659 44643973 2314 gain 3279 TRPM2 Y 1 4 0.000112689 55.01 303 21 44643974 44657372 13398 het loss 3161 TRPM2 Y 1 1 0.13732578 13.21 304 21 44643975 44657372 13397 gain 3127 TRPM2 Y 0 5 1.16E−07 152.56 305 21 44643975 44657372 13397 gain 3185 TRPM2 Y 0 5 1.16E−07 152.56 306 21 44643975 44657372 13397 gain 3200 TRPM2 Y 0 5 1.16E−07 152.56 307 21 44643975 44657372 13397 gain 3205 TRPM2 Y 0 5 1.16E−07 152.56 308 21 44643975 44657372 13397 gain 3279 TRPM2 Y 0 5 1.16E−07 152.56 309 21 44657373 44660198 2825 gain 3127 TRPM2 Y 0 3 2.49E−05 94.48 310 21 44657373 44660198 2825 gain 3200 TRPM2 Y 0 3 2.49E−05 94.48 311 21 44657373 44660198 2825 gain 3279 TRPM2 Y 0 3 2.49E−05 94.48 312 21 44660199 44666832 6633 gain 3127 TRPM2 Y 0 4 2.49E−05 123.12 313 21 44660199 44666832 6633 gain 3200 TRPM2 Y 0 4 2.49E−05 123.12 314 21 44660199 44666832 6633 gain 3205 TRPM2 Y 0 4 2.49E−05 123.12 315 21 44660199 44666832 6633 gain 3279 TRPM2 Y 0 4 2.49E−05 123.12 316 21 44666833 44669596 2763 gain 3127 TRPM2 Y 0 3 2.49E−05 94.48 317 21 44666833 44669596 2763 gain 3205 TRPM2 Y 0 3 2.49E−05 94.48 318 21 44666833 44669596 2763 gain 3279 TRPM2 Y 0 3 2.49E−05 94.48 319 21 44669597 44671482 1885 gain 3205 TRPM2 Y 0 2 0.005115965 66.59 320 21 44669597 44671482 1885 gain 3279 TRPM2 Y 0 2 0.005115965 66.59 321 21 44671483 44681194 9711 gain 3205 TRPM2 Y 0 1 0.005115965 39.43 322 21 45348895 45354820 5925 het loss 3179 ADARB1 N 0 1 0.005115965 39.43 323 22 37689058 37715385 26327 gain 3169 APOBEC3A Y 0 1 0.005115965 39.43 324 APOBEC3A B APOBEC3B 22 39257585 39261621 4036 het loss 3005 MKL1 N 0 1 0.005115965 39.43 325 22 40642402 40655210 12808 gain 3205 TNFRSF13C Y 0 1 0.005115965 39.43 326 22 40655820 40659632 3812 gain 3185 N 0 2 0.005115965 66.59 327 22 40655820 40659632 3812 gain 3205 N 0 2 0.005115965 66.59 328 22 40659633 40663049 3416 gain 3127 N 0 3 2.49E−05 94.48 329 22 40659633 40663049 3416 gain 3185 N 0 3 2.49E−05 94.48 330 22 40659633 40663049 3416 gain 3205 N 0 3 2.49E−05 94.48 331 22 40663050 40668079 5029 gain 3127 CENPM Y 0 5 1.16E−07 152.56 332 22 40663050 40668079 5029 gain 3185 CENPM Y 0 5 1.16E−07 152.56 333 22 40663050 40668079 5029 gain 3190 CENPM Y 0 5 1.16E−07 152.56 334 22 40663050 40668079 5029 gain 3202 CENPM Y 0 5 1.16E−07 152.56 335 22 40663050 40668079 5029 gain 3205 CENPM Y 0 5 1.16E−07 152.56 336 22 40668080 40671866 3786 gain 3127 CENPM Y 0 3 2.49E−05 94.48 337 22 40668080 40671866 3786 gain 3185 CENPM Y 0 3 2.49E−05 94.48 338 22 40668080 40671866 3786 gain 3205 CENPM Y 0 3 2.49E−05 94.48 339 22 40671867 40673250 1383 gain 3185 CENPM Y 0 2 0.005115965 66.59 340 22 40671867 40673250 1383 gain 3205 CENPM Y 0 2 0.005115965 66.59 341 22 40673251 40675788 2537 gain 3205 N 0 1 0.005115965 39.43 342 23 232907 234429 1522 het loss 3007 PPP2R3B N 0 1 0.005115965 39.43 343 23 7585301 7769322 184021 gain 3172 N 5 1 0.358539546 2.63 344 23 7769323 7773949 4626 gain 3172 VCX Y 7 1 0.447101793 1.88 345 23 7773982 7779354 5372 het loss 3132 N 0 3 2.49E−05 94.48 346 23 7773982 7779354 5372 het loss 3171 N 0 3 2.49E−05 94.48 347 23 7773982 7779354 5372 het loss 3204 N 0 3 2.49E−05 94.48 348 23 7773982 7779353 5371 gain 3172 N 5 1 0.358539546 2.63 349 23 7779354 7815400 36046 gain 3172 N 6 1 0.404443314 2.19 350 23 7779355 8093113 313758 het loss 3171 MIR651 Y 0 1 0.005115965 39.43 351 PNPLA4 23 7815401 7830994 15593 gain 3172 PNPLA4 Y 7 1 0.447101793 1.88 352 23 48358646 48408854 50208 het loss 3009 N 0 1 0.005115965 39.43 353 23 64710574 64725828 15254 gain 3125 N 0 1 0.005115965 39.43 354 23 73083877 73086192 2315 hom loss 3193 JPX N 1 2 0.014314826 26.77 355 23 73083877 73086192 2315 hom loss 3200 JPX N 1 2 0.014314826 26.77 356 23 122337025 122340879 3854 hom loss 3125 GRIA3 N 0 1 0.005115965 39.43 357 23 148452844 148461889 9045 het loss 3163 N 7 2 0.129983268 3.8 358 23 148452844 148461889 9045 het loss 3205 N 7 2 0.129983268 3.8 359 23 148459108 148461889 2781 hom loss 3144 N 0 2 0.005115965 66.59 360 23 148459108 148461889 2781 hom loss 3193 N 0 2 0.005115965 66.59 361 23 149901706 149902701 995 gain 3117 HMGB3 Y 0 2 0.005115965 66.59 362 23 149901706 149902701 995 gain 3118 HMGB3 Y 0 2 0.005115965 66.59 363

Table 2 is identical to Table 1, with a number of exceptions. Firstly, the CNV coordinates listed refer to the actual CNV-subregions found to be unique or significantly different between the disease and normal cohorts, as opposed to Table 1, which lists the original CNVs. Secondly, an extra column details whether genic CNV-subregions of interest overlap an exon or not. Third and fourth, 2 extra columns detail the number of normal cases and the number of disease cases that harbor the relevant CNV-subregion. Finally, 2 columns report Fisher's 2-tailed Exact Test (FET) and the odds ratio (OR). Standard chromosomal numbering used by those skilled in the art is used in Table 2 for the autosomal chromosomes (1-22) but, for convenience with analysis methods, chromosome X is designated as chromosome 23 herein. All coordinates are in hg18.

TABLE 3 A non-redundant list of genes listed in Table 2 RefSeq NCBI Gene Gene Exon Gene Gene # Symbol overlap ID Description RefSeq Summary (GN) ADARB1 intronic 104 double- This gene encodes the enzyme responsible for pre-mRNA 2 stranded editing of the glutamate receptor subunit B by site-specific RNA-specific deamination of adenosines. Studies in rat found that this editase 1 enzyme acted on its own pre-mRNA molecules to convert an isoform 1 AA dinucleotide to an AI dinucleotide which resulted in a new splice site. Alternative splicing of this gene results in several transcript variants, some of which have been characterized by the presence or absence of an ALU cassette insert and a short or long C-terminal region. [provided by RefSeq, July 2008]. Transcript Variant: This variant (1), also known as ADAR2a-L1 or DRADA2a, lacks the ALU cassette insert and contains the long C-terminal region, as compared to variant 2. The resulting isoform (1), also known as hRED1- Short, lacks an internal segment, compared to isoform 2. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. ##RefSeq- Attributes-START## undergoes RNA editing :: PMID: 11717408, 12045112 ##RefSeq-Attributes-END## Transcript exon combination :: AB194370.1, U76420.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025084, ERS025085 [ECO:0000348] AGBL4 intronic 84871 cytosolic N/A 3 carboxypeptidase 6 APOBEC3A exonic 200315 DNA dC->dU- This gene is a member of the cytidine deaminase gene family. 4 editing It is one of seven related genes or pseudogenes found in a enzyme cluster, thought to result from gene duplication, on APOBEC-3A chromosome 22. Members of the cluster encode proteins that isoform a are structurally and functionally related to the C to U RNA- editing cytidine deaminase APOBEC1. The protein encoded by this gene lacks the zinc binding activity of other family members. The protein plays a role in immunity, by restricting transmission of foreign DNA such as viruses. One mechanism of foreign DNA restriction is deamination of foreign double- stranded DNA cytidines to uridines, which leads to DNA degradation. However, other mechanisms are also thought to be involved, as anti-viral effect is not dependent on deaminase activity. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, July 2012]. Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (a). Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: U03891.2, BC126416.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025084 [ECO:0000348] APOBEC3A B intronic 100913187 probable DNA This gene is a member of the cytidine deaminase gene family. 5 dC->dU- It is one of seven related genes or pseudogenes found in a editing cluster, thought to result from gene duplication, on enzyme chromosome 22. Members of the cluster encode proteins that APOBEC-3A are structurally and functionally related to the C to U RNA- editing cytidine deaminase APOBEC1. The protein encoded by this gene lacks the zinc binding activity of other family members. The protein plays a role in immunity, by restricting transmission of foreign DNA such as viruses. One mechanism of foreign DNA restriction is deamination of foreign double- stranded DNA cytidines to uridines, which leads to DNA degradation. However, other mechanisms are also thought to be involved, as anti-viral effect is not dependent on deaminase activity. The protein encoded by this gene is the same as that encoded by APOBEC3A; however, this gene is a hybrid gene that results from the deletion of approximately 29.5 kb of sequence between the APOBEC3A gene and the adjacent gene APOBEC3B. The breakpoints of the deletion are within the two genes, so the deletion hybrid is predicted to have the promoter and coding region of APOBEC3A, but the 3′ UTR of APOBEC3B. [provided by RefSeq, July 2012]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. RNAseq introns :: single sample supports all introns ERS025081, ERS025084 [ECO:0000348] APOBEC3B exonic 9582 DNA dC->dU- This gene is a member of the cytidine deaminase gene family. 6 editing It is one of seven related genes or pseudogenes found in a enzyme cluster, thought to result from gene duplication, on APOBEC-3B chromosome 22. Members of the cluster encode proteins that isoform a are structurally and functionally related to the C to U RNA- editing cytidine deaminase APOBEC1. It is thought that the proteins may be RNA editing enzymes and have roles in growth or cell cycle control. A hybrid gene results from the deletion of approximately 29.5 kb of sequence between this gene, APOBEC3B, and the adjacent gene APOBEC3A. The breakpoints of the deletion are within the two genes, so the deletion allele is predicted to have the promoter and coding region of APOBEC3A, but the 3′ UTR of APOBEC3B. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, July 2012]. Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (a). Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: AY743217.1 [ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025081, ERS025082 [ECO:0000350] APOLD1 exonic 81575 apolipoprotein APOLD1 is an endothelial cell early response protein that 7 L domain- may play a role in regulation of endothelial cell signaling and containing vascular function (Regard et al., 2004 [PubMed protein 1 15102925]). [supplied by OMIM, December 2008]. Transcript isoform 1 Variant: This variant (1) represents the longer transcript and encodes the longer isoform (1). Sequence Note: This RefSeq record was created from transcript and genomic sequence data to make the sequence consistent with the reference genome assembly. The extent of this transcript is supported by transcript alignments. Transcript exon combination :: BC042478.1, DR000985.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025086 [ECO:0000348] ARHGEF7 exonic 8874 rho guanine Rho GTPases play a fundamental role in numerous cellular 8 nucleotide processes triggered by extracellular stimuli that work through exchange G protein coupled receptors. The encoded protein belongs to a factor 7 family of cytoplasmic proteins that activate the Ras-like isoform a family of Rho proteins by exchanging bound GDP for GTP. It forms a complex with the small GTP binding protein Rac1 and recruits Rac1 to membrane ruffles and to focal adhesions. This protein can induce membrane ruffling. Multiple alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, July 2008]. Transcript Variant: This variant (1) differs in the 5′ UTR, 3′ UTR, coding region, and uses a downstream start codon, compared to variant 3. Both variants 1 and 5 encode isoform a, which has a shorter N-terminus and a longer and distinct C-terminus, compared to isoform c. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: D63476.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025082 [ECO:0000348] ASTN2 intronic 23245 astrotactin-2 This gene encodes a protein that is expressed in the brain and 9 isoform a may function in neuronal migration, based on functional precursor studies of the related astrotactin 1 gene in human and mouse. A deletion at this locus has been associated with schizophrenia. Multiple transcript variants encoding different proteins have been found for this locus. [provided by RefSeq, May 2010]. Transcript Variant: This variant (1) represents the longest transcript and encodes the longest isoform (a). Transcript exon combination :: BC146756.1, AB014534.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025082 [ECO:0000348] AUH exonic 549 methylglutaconyl- The methylglutaconyl-CoA hydratase, mitochondrial protein 10 CoA binds to the AU-rich element (ARE), a common element hydratase, found in the 3′ UTR of rapidly decaying mRNA such as c-fos, mitochondrial c-myc and granulocyte/macrophage colony stimulating precursor factor. ARE elements are involved in directing RNA to rapid degradation and deadenylation. AUH is also homologous to enol-CoA hydratase, an enzyme involved in fatty acid degradation, and has been shown to have intrinsic hydratase enzymatic activity. AUH is thus a bifunctional chimera between RNA binding and metabolic enzyme activity. A possible subcellular localization in the mitochondria has been demonstrated for the mouse homolog of this protein which shares 92% identity with the human protein. It has been suggested that AUH may have a novel role as a mitochondrial located AU-binding protein. Human AUH is expressed as a single mRNA species of 1.8 kb, and translated as a 40-kDa precursor protein which is subsequently processed to a 32- kDa mature form. [provided by RefSeq, May 2010]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. ##RefSeq- Attributes-START## gene product(s) localized to mito. :: reported by MitoCarta ##RefSeq-Attributes-END## Transcript exon combination :: X79888.1, AL533438.3 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025084, ERS025088 [ECO:0000348] BACH1 exonic 571 BTB Domain This gene encodes a transcription factor that belongs to the 11 And CNC cap'n'collar type of basic region leucine zipper factor family Homolog 1 (CNC-bZip). The encoded protein contains broad complex, tramtrack, bric-a-brac/poxvirus and zinc finger (BTB/POZ) domains, which is atypical of CNC-bZip family members. These BTB/POZ domains facilitate protein-protein interactions and formation of homo- and/or hetero-oligomers. When this encoded protein forms a heterodimer with MafK, it functions as a repressor of Maf recognition element (MARE) and transcription is repressed. Multiple alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, May 2009]. Transcript Variant: This variant (3), also named BACH1t, differs in the 5′ UTR, 3′ coding region and 3′ UTR (compared to variant 1). This variant is represented as non-coding because the use of the 5′- most supported translational start codon, as used in variant 1, renders the transcript a candidate for nonsense-mediated mRNA decay (NMD). This transcript represents the splice variant reported by Kanezaki et al. (PMID: 11069897). Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. RNAseq introns :: mixed/partial sample support ERS025084, ERS025088 [ECO:0000350] BDKRB2 intronic 624 B2 bradykinin This gene encodes a receptor for bradykinin. The 9 aa 12 receptor bradykinin peptide elicits many responses including vasodilation, edema, smooth muscle spasm and pain fiber stimulation. This receptor associates with G proteins that stimulate a phosphatidylinositol-calcium second messenger system. Alternate start codons result in two isoforms of the protein. [provided by RefSeq, July 2008]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: DC369062.1, DC417219.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025090 [ECO:0000348] BMPR2 intronic 659 bone This gene encodes a member of the bone morphogenetic 13 morphogenetic protein (BMP) receptor family of transmembrane protein serine/threonine kinases. The ligands of this receptor are receptor type- BMPs, which are members of the TGF-beta superfamily. 2 precursor BMPs are involved in endochondral bone formation and embryogenesis. These proteins transduce their signals through the formation of heteromeric complexes of two different types of serine (threonine) kinase receptors: type I receptors of about 50-55 kD and type II receptors of about 70-80 kD. Type II receptors bind ligands in the absence of type I receptors, but they require their respective type I receptors for signaling, whereas type I receptors require their respective type II receptors for ligand binding. Mutations in this gene have been associated with primary pulmonary hypertension, both familial and fenfluramine-associated, and with pulmonary venoocclusive disease. [provided by RefSeq, July 2008]. Sequence Note: This RefSeq record was created from transcript and genomic sequence data to make the sequence consistent with the reference genome assembly. The extent of this transcript is supported by transcript alignments. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: BC052985.2, AK292430.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025082 [ECO:0000348] BTBD17 exonic 388419 BTB/POZ N/A 14 domain- containing protein 17 precursor C17orf77 exonic 146723 uncharacterized N/A 15 protein Cl7orf77 precursor CAPZB intronic 832 F-actin- This gene encodes the beta subunit of the barbed-end actin 16 capping binding protein, which belongs to the F-actin capping protein protein family. The capping protein is a heterodimeric actin capping subunit beta protein that blocks actin filament assembly and disassembly isoform 1 at the fast growing (barbed) filament ends and functions in regulating actin filament dynamics as well as in stabilizing actin filament lengths in muscle and nonmuscle cells. A pseudogene of this gene is located on the long arm of chromosome 2. Multiple alternatively spliced transcript variants encoding different isoforms have been found. [provided by RefSeq, August 2013]. Transcript Variant: This variant (1) encodes isoform 1. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: BC107752.1, BM451686.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025088 [ECO:0000348] CCDC41 exonic 51134 centrosomal N/A 17 protein of 83 kDa CD300A exonic 11314 CMRF35-like This gene encodes a member of the CD300 glycoprotein 18 molecule 8 family of cell surface proteins found on leukocytes involved isoform 1 in immune response signaling pathways. This gene is located precursor on chromosome 17 in a cluster with all but one of the other family members. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, February 2012]. Transcript Variant: This variant (1) represents the longer transcript and encodes the longer protein (isoform 1), also referred to as IRC1a. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: BC032352.1, AL531420.3 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025083 [ECO:0000348] CD300C exonic 10871 CMRF35-like The CMRF35 antigen, which was identified by reactivity with 19 molecule 6 a monoclonal antibody, is present on monocytes, neutrophils, precursor and some T and B lymphocytes (Jackson et al., 1992 [PubMed 1349532]). [supplied by OMIM, March 2008]. Transcript exon combination :: BC022279.1, BM922826.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025084, ERS025087 [ECO:0000348] CD300E exonic 342510 CMRF35-like This gene encodes a member of the CD300 glycoprotein 20 molecule 2 family of cell surface proteins expressed on myeloid cells. precursor The protein interacts with the TYRO protein tyrosine kinase- binding protein and is thought to act as an activating receptor. [provided by RefSeq, November 2012]. Sequence Note: This RefSeq record was created from transcript and genomic sequence data to make the sequence consistent with the reference genome assembly. The genomic coordinates used for the transcript record were based on transcript alignments. An in-frame AUG is located 41 codons upstream of the annotated translation start site but is not being annotated as a start site since it is not conserved and is in a weak Kozak sequence context. ##RefSeq-Attributes-START## CDS uses downstream in-frame AUG :: downstream AUG is associated with N-terminal localization signal ##RefSeq-Attributes- END## Transcript exon combination :: AK303545.1, BX648376.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025084, ERS025088 [ECO:0000348] CD300LB exonic 124599 CMRF35-like CD300LB is a nonclassical activating receptor of the 21 molecule 7 immunoglobulin (Ig) superfamily expressed on myeloid cells precursor (Martinez-Barriocanal and Sayos, 2006 [PubMed 16920917]). [supplied by OMIM, March 2008]. CCDS Note: The coding region has been updated to shorten the N-terminus to one that is more supported by available conservation data and paralogous family members. The update has a predicted N-terminal signal peptide, which is consistent with functional support for the protein (e.g., PMIDs 16920917, 19359216). Transcript exon combination :: BC028091.1, AY359025.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025084, ERS025088 [ECO:0000348] ##RefSeq- Attributes-START## CDS uses downstream in-frame AUG :: downstream AUG is associated with N-terminal localization signal ##RefSeq-Attributes-END## CD300LD exonic 100131439 CMRF35-like N/A 22 molecule 4 precursor CD300LF exonic 146722 CMRF35-like CD300LF is an inhibitory receptor of the Ig superfamily 23 molecule 1 expressed on myeloid cells. It mediates negative regulatory precursor signals by recruiting SHP1 (PTPN6; MIM 176883) or SHIP (INPP5D; MIM 601582) (Sui et al., 2004 [PubMed 15184070]; Alvarez-Errico et al., 2004 [PubMed 15549731]). [supplied by OMIM, March 2008]. Sequence Note: The RefSeq transcript and protein were derived from genomic sequence to make the sequence consistent with the reference genome assembly. The genomic coordinates used for the transcript record were based on alignments. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: AF251706.1, AY358545.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025084 [ECO:0000348] CDKN1B exonic 1027 cyclin- This gene encodes a cyclin-dependent kinase inhibitor, which 24 dependent shares a limited similarity with CDK inhibitor CDKN1A/p21. kinase The encoded protein binds to and prevents the activation of inhibitor 1B cyclin E-CDK2 or cyclin D-CDK4 complexes, and thus controls the cell cycle progression at G1. The degradation of this protein, which is triggered by its CDK dependent phosphorylation and subsequent ubiquitination by SCF complexes, is required for the cellular transition from quiescence to the proliferative state. [provided by RefSeq, July 2008]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: BC001971.1, AY004255.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025082 [ECO:0000348] CENPM exonic 79019 centromere The centromere is a specialized chromatin domain, present 25 protein M throughout the cell cycle, that acts as a platform on which the isoform a transient assembly of the kinetochore occurs during mitosis. All active centromeres are characterized by the presence of long arrays of nucleosomes in which CENPA (MIM 117139) replaces histone H3 (see MIM 601128). CENPM is an additional factor required for centromere assembly (Foltz et al., 2006 [PubMed 16622419]). [supplied by OMIM, March 2008]. Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (a). Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: BC000705.2, BC007495.2 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025085, ERS025088 [ECO:0000348] COG4 exonic 25839 conserved The protein encoded by this gene is a component of an 26 oligomeric oligomeric protein complex involved in the structure and Golgi function of the Golgi apparatus. Defects in this gene may be a complex cause of congenital disorder of glycosylation type IIj. Two subunit 4 transcript variants encoding different isoforms have been isoform 1 found for this gene. [provided by RefSeq, August 2010]. Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (1). Transcript exon combination :: BC072438.1, AK022874.1 [ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025081, ERS025082 [ECO:0000350] COMMD6 exonic 170622 COMM COMMD6 belongs to a family of NF-kappa-B (see RELA; 27 domain- MIM 164014)-inhibiting proteins characterized by the containing presence of a COMM domain (see COMMD1; MIM 607238) protein 6 (de Bie et al., 2006 [PubMed 16573520]). [supplied by isoform a OMIM, March 2009]. Transcript exon combination :: HY028175.1, DW440523.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025088 [ECO:0000348] CRADD exonic 8738 death domain- The protein encoded by this gene is a death domain 28 containing (CARD/DD)-containing protein and has been shown to protein induce cell apoptosis. Through its CARD domain, this protein CRADD interacts with, and thus recruits, caspase 2/ICH1 to the cell death signal transduction complex that includes tumor necrosis factor receptor 1 (TNFR1A), RIPK1/RIP kinase, and numbers of other CARD domain-containing proteins. [provided by RefSeq, July 2008]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: BX480215.1, BC017042.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025083 [ECO:0000348] CREBL2 exonic 1389 cAMP- cAMP response element (CRE)-binding protein-like-2 29 responsive (CREBL2) was identified in a search to find genes in a element- commonly deleted region on chromosome 12p13 flanked by binding ETV6 and CDKN1B genes, frequently associated with protein-like 2 hematopoietic malignancies, as well as breast, non-small-cell lung and ovarian cancers. CREBL2 shares a 41% identity with CRE-binding protein (CREB) over a 48-base long region which encodes the bZip domain of CREB. The bZip domain consists of about 30 amino acids rich in basic residues involved in DNA binding, followed by a leucine zipper motif involved in protein dimerization. This suggests that CREBL2 encodes a protein with DNA binding capabilities. The occurance of CREBL2 deletion in malignancy suggests that CREBL2 may act as a tumor suppressor gene. [provided by RefSeq, July 2008]. Transcript exon combination :: BC106052.1, AF039081.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025082 [ECO:0000348] DNAI2 exonic 64446 dynein The protein encoded by this gene belongs to the dynein 30 intermediate intermediate chain family, and is part of the dynein complex chain 2, of respiratory cilia and sperm flagella. Mutations in this gene axonemal are associated with primary ciliary dyskinesia type 9. isoform 1 Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, March 2010]. Transcript Variant: This variant (1) encodes the longer isoform (1). Transcript exon combination :: AF250288.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025085 [ECO:0000348] ##RefSeq- Attributes-START## NMD candidate :: translation inferred from conservation ##RefSeq-Attributes-END## DNER intronic 92737 delta and N/A 31 Notch-like epidermal growth factor- related receptor precursor DUSP16 exonic 80824 dual This gene encodes a mitogen-activated protein kinase 32 specificity phosphatase that is a member of the dual specificity protein protein phosphatase subfamily. These phosphatases inactivate their phosphatase target kinases by dephosphorylating both the 16 phosphoserine/threonine and phosphotyrosine residues. The encoded protein specifically regulates the c-Jun amino- terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) pathways. [provided by RefSeq, May 2010]. Sequence Note: This RefSeq record was created from transcript and genomic sequence data to make the sequence consistent with the reference genome assembly. The genomic coordinates used for the transcript record were based on transcript alignments. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: AF506796.1, AB052156.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025084, ERS025088 [ECO:0000348] ECRP exonic 643332 N/A N/A 33 EDIL3 intronic 10085 EGF-like The protein encoded by this gene is an integrin ligand. It 34 repeat and plays an important role in mediating angiogenesis and may be discoidin I- important in vessel wall remodeling and development. It also like domain- influences endothelial cell behavior. [provided by RefSeq, July containing 2008]. Transcript Variant: This variant (1) encodes the longer protein 3 isoform (1). Sequence Note: This RefSeq record was created isoform 1 from transcript and genomic sequence data to make the precursor sequence consistent with the reference genome assembly. The genomic coordinates used for the transcript record were based on transcript alignments. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: BC030828.1, U70312.1 [ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025081, ERS025082 [ECO:0000350] EEA1 exonic 8411 early N/A 35 endosome antigen 1 EHF both 26298 ETS This gene encodes a protein that belongs to an ETS 36 homologous transcription factor subfamily characterized by epithelial- factor isoform specific expression (ESEs). The encoded protein acts as a 1 precursor transcriptional repressor and may be involved in epithelial differentiation and carcinogenesis. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, June 2011]. Transcript Variant: This variant (1) encodes the longest isoform (1). Sequence Note: This RefSeq record was created from transcript and genomic sequence data to make the sequence consistent with the reference genome assembly. The genomic coordinates used for the transcript record were based on transcript alignments. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: AK310867.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025084, ERS025086 [ECO:0000348] EMB exonic 133418 embigin This gene encodes a transmembrane glycoprotein that is a 37 precursor member of the immunoglobulin superfamily. The encoded protein may be involved in cell growth and development by mediating interactions between the cell and extracellular matrix. A pseudogene of this gene is found on chromosome 1. [provided by RefSeq, January 2009]. Transcript exon combination :: BC059398.1, AK300860.1 [ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025081, ERS025082 [ECO:0000350] ETV6 exonic 2120 transcription This gene encodes an ETS family transcription factor. The 38 factor ETV6 product of this gene contains two functional domains: a N- terminal pointed (PNT) domain that is involved in protein- protein interactions with itself and other proteins, and a C- terminal DNA-binding domain. Gene knockout studies in mice suggest that it is required for hematopoiesis and maintenance of the developing vascular network. This gene is known to be involved in a large number of chromosomal rearrangements associated with leukemia and congenital fibrosarcoma. [provided by RefSeq, September 2008]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: BC043399.1, U11732.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025082 [ECO:0000348] FHL2 exonic 2274 four and a half This gene encodes a member of the four-and-a-half-LIM-only 39 LIM domains protein family. Family members contain two highly protein 2 conserved, tandemly arranged, zinc finger domains with four highly conserved cysteines binding a zinc atom in each zinc finger. This protein is thought to have a role in the assembly of extracellular membranes. Also, this gene is down-regulated during transformation of normal myoblasts to rhabdomyosarcoma cells and the encoded protein may function as a link between presenilin-2 and an intracellular signaling pathway. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, August 2011]. Transcript Variant: This variant (1) differs in the 5′ UTR compared to variant 2. Variants 1, 2, 4 and 5 encode the same isoform. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. ##RefSeq-Attributes-START## CDS uses downstream in-frame AUG :: lack of evidence for use of upstream AUG ##RefSeq-Attributes-END## Transcript exon combination :: BC093049.1, AL523628.3 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025084, ERS025088 [ECO:0000348] FLJ26850 intronic 400710 N/A N/A 40 FPR2 exonic 2358 N-formyl N/A 41 peptide receptor 2 FPR3 exonic 2359 N-formyl N/A 42 peptide receptor 3 FUK both 197258 L-fucose The protein encoded by this gene belongs to the GHMP 43 kinase (galacto-, homoserine, mevalonate and phosphomevalonate) kinase family and catalyzes the phosphorylation of L-fucose to form beta-L-fucose 1-phosphate. This enzyme catalyzes the first step in the utilization of free L-fucose in glycoprotein and glycolipid synthesis. L-fucose may be important in mediating a number of cell-cell interactions such as blood group antigen recognition, inflammation, and metastatis. While several transcript variants may exist for this gene, the full-length nature of only one has been described to date. [provided by RefSeq, July 2008]. Transcript exon combination :: AJ441184.1, BC032542.1 [ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025081, ERS025082 [ECO:0000350] GDA exonic 9615 guanine This gene encodes an enzyme responsible for the hydrolytic 44 deaminase deamination of guanine. Studies in rat ortholog suggest this isoform a gene plays a role in microtubule assembly. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, November 2011]. Transcript Variant: This variant (1) encodes the longest isoform (a). Sequence Note: This RefSeq record was created from transcript and genomic sequence data to make the sequence consistent with the reference genome assembly. The genomic coordinates used for the transcript record were based on transcript alignments. RNAseq introns :: mixed/partial sample support ERS025082, ERS025083 [ECO:0000350] GDPD4 exonic 220032 glycerophosphodiester N/A 45 phosphodiesterase domain- containing protein 4 GPATCH2 intronic 55105 G patch N/A 46 domain- containing protein 2 GPC5 intronic 2262 glypican-5 Cell surface heparan sulfate proteoglycans are composed of a 47 precursor membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican- related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation. [provided by RefSeq, July 2008]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: BC030584.1, BC039730.1 [ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025082, ERS025083 [ECO:0000350] GPR19 exonic 2842 probable G- N/A 48 protein coupled receptor 19 GPR142 exonic 350383 probable G- GPR142 is a member of the rhodopsin family of G protein- 49 protein coupled receptors (GPRs) (Fredriksson et al., 2003 [PubMed coupled 14623098]). [supplied by OMIM, March 2008]. Transcript exon receptor 142 combination :: AB196530.1, AY288421.1 [ECO:0000332] GPRC5C exonic 55890 G-protein The protein encoded by this gene is a member of the type 3 G 50 coupled protein-coupled receptor family. Members of this superfamily receptor are characterized by a signature 7-transmembrane domain family C motif. The specific function of this protein is unknown; group 5 however, this protein may mediate the cellular effects of member C retinoic acid on the G protein signal transduction cascade. isoform a Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, July 2008]. Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (a). Transcript exon combination :: BC110848.1, AK131210.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025083 [ECO:0000348] GRIA3 intronic 2892 glutamate Glutamate receptors are the predominant excitatory 51 receptor 3 neurotransmitter receptors in the mammalian brain and are isoform 1 activated in a variety of normal neurophysiologic processes. precursor These receptors are heteromeric protein complexes composed of multiple subunits, arranged to form ligand-gated ion channels. The classification of glutamate receptors is based on their activation by different pharmacologic agonists. The subunit encoded by this gene belongs to a family of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate)- sensitive glutamate receptors, and is subject to RNA editing (AGA->GGA; R->G). Alternative splicing at this locus results in different isoforms, which may vary in their signal transduction properties. [provided by RefSeq, July 2008]. Transcript Variant: This variant (1) encodes isoform 1 (also known as flip isoform). RNA editing (AGA->GGA) changes Arg775Gly. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. ##RefSeq-Attributes-START## undergoes RNA editing :: PMID: 10688364, 7992055 ##RefSeq-Attributes-END## Transcript exon combination :: U10301.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025082, ERS025084 [ECO:0000348] GTPBP4 exonic 23560 nucleolar GTP-binding proteins are GTPases and function as molecular 52 GTP-binding switches that can flip between two states: active, when GTP is protein 1 bound, and inactive, when GDP is bound. ‘Active’ in this context usually means that the molecule acts as a signal to trigger other events in the cell. When an extracellular ligand binds to a G-protein-linked receptor, the receptor changes its conformation and switches on the trimeric G proteins that associate with it by causing them to eject their GDP and replace it with GTP. The switch is turned off when the G protein hydrolyzes its own bound GTP, converting it back to GDP. But before that occurs, the active protein has an opportunity to diffuse away from the receptor and deliver its message for a prolonged period to its downstream target [provided by RefSeq, July 2008]. Transcript exon combination :: AK001552.1, AK222861.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025082 [ECO:0000348] HCN1 exonic 348980 potassium/sodium The membrane protein encoded by this gene is a 53 hyperpolarization- hyperpolarization-activated cation channel that contributes to activated the native pacemaker currents in heart and neurons. The cyclic encoded protein can homodimerize or heterodimerize with nucleotide- other pore-forming subunits to form a potassium channel. gated channel This channel may act as a receptor for sour tastes. [provided 1 by RefSeq, October 2011]. Sequence Note: This RefSeq record was created from transcript and genomic sequence data to make the sequence consistent with the reference genome assembly. The genomic coordinates used for the transcript record were based on transcript alignments. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: AF488549.1, AF064876.1 [ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025081, ERS025082 [ECO:0000350] HEXA exonic 3073 beta- This gene encodes the alpha subunit of the lysosomal enzyme 54 hexosaminidase beta-hexosaminidase that, together with the cofactor GM2 subunit activator protein, catalyzes the degradation of the ganglioside alpha GM2, and other molecules containing terminal N-acetyl preproprotein hexosamines. Beta-hexosaminidase is composed of two subunits, alpha and beta, which are encoded by separate genes. Both beta-hexosaminidase alpha and beta subunits are members of family 20 of glycosyl hydrolases. Mutations in the alpha or beta subunit genes lead to an accumulation of GM2 ganglioside in neurons and neurodegenerative disorders termed the GM2 gangliosidoses. Alpha subunit gene mutations lead to Tay-Sachs disease (GM2-gangliosidosis type I). [provided by RefSeq, July 2009]. Sequence Note: This RefSeq record was created from transcript and genomic sequence data because no single transcript was available for the full length of the gene. The extent of this transcript is supported by transcript alignments. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: M13520.1, CR627386.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025084, ERS025088 [ECO:0000348] HK2 exonic 3099 hexokinase-2 Hexokinases phosphorylate glucose to produce glucose-6- 55 phosphate, the first step in most glucose metabolism pathways. This gene encodes hexokinase 2, the predominant form found in skeletal muscle. It localizes to the outer membrane of mitochondria. Expression of this gene is insulin- responsive, and studies in rat suggest that it is involved in the increased rate of glycolysis seen in rapidly growing cancer cells. [provided by RefSeq, April 2009]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: BC064369.1, AF148513.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025083, ERS025084 [ECO:0000348] HMGB3 exonic 3149 high mobility HMGB3 belongs to the high mobility group (HMG) protein 56 group protein superfamily. Like HMG1 (MIM 163905) and HMG2 (MIM B3 163906), HMGB3 contains DNA-binding HMG box domains and is classified into the HMG box subfamily. Members of the HMG box subfamily are thought to play a fundamental role in DNA replication, nucleosome assembly and transcription (Wilke et al., 1997 [PubMed 9370291]; Nemeth et al., 2006 [PubMed 16945912]). [supplied by OMIM, March 2008]. Transcript exon combination :: Y10043.1, BG176733.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025082 [ECO:0000348] HPR exonic 3250 haptoglobin- This gene encodes a haptoglobin-related protein that binds 57 related protein hemoglobin as efficiently as haptoglobin. Unlike haptoglobin, precursor plasma concentration of this protein is unaffected in patients with sickle cell anemia and extensive intravascular hemolysis, suggesting a difference in binding between haptoglobin- hemoglobin and haptoglobin-related protein-hemoglobin complexes to CD163, the hemoglobin scavenger receptor. This protein may also be a clinically important predictor of recurrence of breast cancer. [provided by RefSeq, October 2011]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: CB147217.1, CB122261.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025084, ERS025088 [ECO:0000348] HTATSF1P2 exonic 401233 N/A N/A 58 IDI2 exonic 91734 isopentenyl- N/A 59 diphosphate Delta- isomerase 2 IDI2-AS1 exonic 55853 N/A N/A 60 IDO2 intronic 169355 indoleamine Along with the enzymes encoded by the INDO (MIM 61 2,3- 147435) and TDO2 (MIM 191070) genes, the enzyme dioxygenase 2 encoded by the INDOL1 gene metabolizes tryptophan in the kynurenine pathway (Ball et al., 2007 [PubMed 17499941]). [supplied by OMIM, February 2011]. Sequence Note: The RefSeq transcript 3′ UTR was derived from genomic sequence to make the sequence consistent with the reference genome assembly. The genomic coordinates used were based on transcript alignments. IFNLR1 exonic 163702 interferon The protein encoded by this gene belongs to the class II 62 lambda cytokine receptor family. This protein forms a receptor receptor 1 complex with interleukine 10 receptor, beta (IL10RB). The isoform 1 receptor complex has been shown to interact with three precursor closely related cytokines, including interleukin 28A (IL28A), interleukin 28B (IL28B), and interleukin 29 (IL29). The expression of all three cytokines can be induced by viral infection. The cells overexpressing this protein have been found to have enhanced responses to IL28A and IL29, but decreased response to IL28B. Three alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, July 2008]. Transcript Variant: This variant (1) represents the longest transcript and it encodes the longest protein (isoform 1). Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: AF439325.1, AK160364.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025084 [ECO:0000348] IQCB1 exonic 9657 IQ This gene encodes a nephrocystin protein that interacts with 63 calmodulin- calmodulin and the retinitis pigmentosa GTPase regulator binding motif- protein. The encoded protein has a central coiled-coil region containing and two calmodulin-binding IQ domains. It is localized to the protein 1 primary cilia of renal epithelial cells and connecting cilia of isoform a photoreceptor cells. The protein is thought to play a role in ciliary function. Defects in this gene result in Senior-Loken syndrome type 5. Alternative splicing results in multiple transcript variants. [provided by RefSeq, November 2009]. Transcript Variant: This variant (1) encodes the longer isoform (a). Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: D25278.1, AY714228.1 [ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025081, ERS025082 [ECO:0000350] JPX intronic 554203 JPX is a nonprotein-coding RNA transcribed from a gene 64 within the X-inactivation center (XIC; MIM 314670) that appears to participate in X chromosome inactivation (Tian et al., 2010 [PubMed 21029862]). [supplied by OMIM, February 2011]. Transcript exon combination :: BC071776.1 [ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025081, ERS025082 [ECO:0000350] KANK1 intronic 23189 KN motif and The protein encoded by this gene belongs to the Kank family 65 ankyrin repeat of proteins, which contain multiple ankyrin repeat domains. domain- This family member functions in cytoskeleton formation by containing regulating actin polymerization. This gene is a candidate protein 1 tumor suppressor for renal cell carcinoma. Mutations in this isoform a gene cause cerebral palsy spastic quadriplegic type 2, a central nervous system development disorder. A t(5; 9) translocation results in fusion of the platelet-derived growth factor receptor beta gene (PDGFRB) on chromosome 5 with this gene in a myeloproliferative neoplasm featuring severe thrombocythemia. Alternative splicing of this gene results in multiple transcript variants. A related pseuodgene has been identified on chromosome 20. [provided by RefSeq, March 2012]. Transcript Variant: This variant (1) represents the shortest transcript but encodes the longer isoform (a, also known as Kank-L). Variants 1, 3 and 4 all encode isoform a. Sequence Note: This RefSeq record was created from transcript and genomic sequence data to make the sequence consistent with the reference genome assembly. The genomic coordinates used for the transcript record were based on transcript alignments. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: AL833161.1, AK292989.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025084, ERS025085 [ECO:0000348] KAT6B exonic 23522 histone The protein encoded by this gene is a histone 66 acetyltransferase acetyltransferase and component of the MOZ/MORF protein KAT6B complex. In addition to its acetyltransferase activity, the isoform 1 encoded protein has transcriptional activation activity in its N-terminal end and transcriptional repression activity in its C- terminal end. This protein is necessary for RUNX2-dependent transcriptional activation and could be involved in brain development. Mutations have been found in patients with genitopatellar syndrome. A translocation of this gene and the CREBBP gene results in acute myeloid leukemias. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, March 2012]. Transcript Variant: This variant (1) represents the longest transcript and encodes the longest isoform (1). Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: AF217500.1, BC150618.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025083, ERS025084 [ECO:0000348] KCTD7 exonic 154881 BTB/POZ This gene encodes a member of the potassium channel 67 domain- tetramerization domain-containing protein family. Family containing members are identified on a structural basis and contain an protein amino-terminal domain similar to the T1 domain present in KCTD7 the voltage-gated potassium channel. Mutations in this gene isoform 1 have been associated with progressive myoclonic epilepsy-3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, January 2011]. Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (1). Sequence Note: This RefSeq record was created from transcript and genomic sequence data to make the sequence consistent with the reference genome assembly. The genomic coordinates used for the transcript record were based on transcript alignments. Transcript exon combination :: AK056631.1, BU902852.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025083 [ECO:0000348] KIF19 exonic 124602 kinesin-like N/A 68 protein KIF19 LARP4B exonic 23185 la-related This gene encodes a member of an evolutionarily conserved 69 protein 4B protein family implicated in RNA metabolism and translation. Members of this family are characterized by the presence of an La motif, which is often located adjacent to one or more RNA recognition motifs (RRM). Together, the two motifs constitute the functional region of the protein and enable its interaction with the RNA substrate. This protein family is divided into five sub-families: the genuine La proteins and four La-related protein (LARP) sub-families. The protein encoded by this gene belongs to LARP sub-family 4. It is a cytoplasmic protein that may play a stimulatory role in translation. [provided by RefSeq, October 2012]. Sequence Note: This RefSeq record was created from transcript and genomic sequence data to make the sequence consistent with the reference genome assembly. The genomic coordinates used for the transcript record were based on transcript alignments. CDS exon combination :: BC152443.1, D86971.2 [ECO:0000331] RNAseq introns :: mixed/partial sample support ERS025088 [ECO:0000350] LOC643339 exonic 643339 N/A N/A 70 LOH12CR1 exonic 118426 loss of N/A 71 heterozygosity 12 chromosomal region 1 protein MALL exonic 7851 MAL-like This gene encodes an element of the machinery for raft- 72 protein mediated trafficking in endothelial cells. The encoded protein, a member of the MAL proteolipid family, predominantly localizes in glycolipid- and cholesterol-enriched membrane (GEM) rafts. It interacts with caveolin-1. [provided by RefSeq, July 2008]. Transcript exon combination :: AK125647.1, AK056616.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025084, ERS025088 [ECO:0000348] MAPK9 exonic 5601 mitogen- The protein encoded by this gene is a member of the MAP 73 activated kinase family. MAP kinases act as an integration point for protein kinase multiple biochemical signals, and are involved in a wide 9 isoform variety of cellular processes such as proliferation, alpha1 differentiation, transcription regulation and development. This kinase targets specific transcription factors, and thus mediates immediate-early gene expression in response to various cell stimuli. It is most closely related to MAPK8, both of which are involved in UV radiation induced apoptosis, thought to be related to the cytochrome c-mediated cell death pathway. This gene and MAPK8 are also known as c-Jun N-terminal kinases. This kinase blocks the ubiquitination of tumor suppressor p53, and thus it increases the stability of p53 in nonstressed cells. Studies of this gene's mouse counterpart suggest a key role in T-cell differentiation. Several alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, September 2008]. Transcript Variant: This variant (JNK2-a1) uses a different acceptor splice site in the last coding exon compared to transcript variant JNK2-a2, resulting in a frameshift and a shorter isoform (JNK2 alpha1) with a different C-terminus, compared to isoform JNK2 alpha2. The JNK2-a1 variant differs from the JNK2-b1 variant in the use of an alternate internal coding exon of the same length. Thus, JNK2 alpha1 isoform is the same length as JNK2 beta1 isoform, with a few aa differences in an internal protein segment. Sequence Note: This RefSeq record was created from transcript and genomic sequence data because no single transcript was available for the full length of the gene. The extent of this transcript is supported by transcript alignments. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. CDS exon combination :: U34821.1 [ECO:0000331] RNAseq introns :: mixed/partial sample support ERS025081, ERS025082 [ECO:0000350] MCEE both 84693 methylmalonyl- The product of this gene catalyzes the interconversion of D- 74 CoA and L-methylmalonyl-CoA during the degradation of epimerase, branched chain amino acids. odd chain-length fatty acids, and mitochondrial other metabolites. Mutations in this gene result in precursor methylmalonyl-CoA epimerase deficiency, which is presented as mild to moderate methylmalonic aciduria. [provided by RefSeq, July 2008]. Transcript exon combination :: BC020825.1, BG567074.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025082 [ECO:0000348] MGAT5 intronic 4249 alpha-1,6- The protein encoded by this gene belongs to the 75 mannosylglycoprotein glycosyltransferase family. It catalyzes the addition of beta- 6- 1,6-N-acetylglucosamine to the alpha-linked mannose of beta-N- biantennary N-linked oligosaccharides present on the newly acetylglucosaminyl- synthesized glycoproteins. It is one of the most important transferase A enzymes involved in the regulation of the biosynthesis of glycoprotein oligosaccharides. Alterations of the oligosaccharides on cell surface glycoproteins cause significant changes in the adhesive or migratory behavior of a cell. Increase in the activity of this enzyme has been correlated with the progression of invasive malignancies. [provided by RefSeq, October 2011]. Sequence Note: This RefSeq record was created from transcript and genomic sequence data to make the sequence consistent with the reference genome assembly. The genomic coordinates used for the transcript record were based on transcript alignments. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: D17716.1, AF113921.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025082 [ECO:0000348] MGC16275 exonic 85001 N/A N/A 76 MGME1 exonic 92667 mitochondrial N/A 77 genome maintenance exonuclease 1 MIR200A exonic 406983 microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs 78 that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein- coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre- miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, September 2009]. Sequence Note: This record represents a predicted microRNA stem-loop as defined by miRBase. Some sequence at the 5′ and 3′ ends may not be included in the intermediate precursor miRNA produced by Drosha cleavage. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. MIR200B exonic 406984 microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs 79 that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein- coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre- miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, September 2009]. Sequence Note: This record represents a predicted microRNA stem-loop as defined by miRBase. Some sequence at the 5′ and 3′ ends may not be included in the intermediate precursor miRNA produced by Drosha cleavage. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. MIR429 exonic 554210 microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs 80 that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein- coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre- miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, September 2009]. Sequence Note: This record represents a predicted microRNA stem-loop as defined by miRBase. Some sequence at the 5′ and 3′ ends may not be included in the intermediate precursor miRNA produced by Drosha cleavage. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. MIR595 exonic 693180 microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs 81 that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein- coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre- miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, September 2009]. Sequence Note: This record represents a predicted microRNA stem-loop as defined by miRBase. Some sequence at the 5′ and 3′ ends may not be included in the intermediate precursor miRNA produced by Drosha cleavage. MIR651 exonic 723779 microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs 82 that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein- coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre- miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, September 2009]. Sequence Note: This record represents a predicted microRNA stem-loop as defined by miRBase. Some sequence at the 5′ and 3′ ends may not be included in the intermediate precursor miRNA produced by Drosha cleavage. MIR3163 exonic 100423029 microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs 83 that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein- coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre- miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, September 2009]. Sequence Note: This record represents a predicted microRNA stem-loop as defined by miRBase. Some sequence at the 5′ and 3′ ends may not be included in the intermediate precursor miRNA produced by Drosha cleavage. MIR3910-1 exonic 100500821 microRNA (miRNAs) are short (20-24 nt) non-coding RNAs 84 that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein- coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre- miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, September 2009]. Sequence Note: This record represents a predicted microRNA stem-loop as defined by miRBase. Some sequence at the 5′ and 3′ ends may not be included in the intermediate precursor miRNA produced by Drosha cleavage. MIR3910-2 exonic 100500902 microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs 85 that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein- coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre- miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, September 2009]. Sequence Note: This record represents a predicted microRNA stem-loop as defined by miRBase. Some sequence at the 5′ and 3′ ends may not be included in the intermediate precursor miRNA produced by Drosha cleavage. MIR4267 exonic 100422994 microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs 86 that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein- coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre- miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, September 2009]. Sequence Note: This record represents a predicted microRNA stem-loop as defined by miRBase. Some sequence at the 5′ and 3′ ends may not be included in the intermediate precursor miRNA produced by Drosha cleavage. MIR4436B1 exonic 100616123 microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs 87 that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein- coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre- miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, September 2009]. Sequence Note: This record represents a predicted microRNA stem-loop as defined by miRBase. Some sequence at the 5′ and 3′ ends may not be included in the intermediate precursor miRNA produced by Drosha cleavage. MIR4436B2 exonic 100847033 microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs 88 that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein- coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre- miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, September 2009]. Sequence Note: This record represents a predicted microRNA stem-loop as defined by miRBase. Some sequence at the 5′ and 3′ ends may not be included in the intermediate precursor miRNA produced by Drosha cleavage. MKL1 intronic 57591 MKL/mycardin- The protein encoded by this gene interacts with the 89 like transcription factor myocardin, a key regulator of smooth protein 1 muscle cell differentiation. The encoded protein is predominantly nuclear and may help transduce signals from the cytoskeleton to the nucleus. This gene is involved in a specific translocation event that creates a fusion of this gene and the RNA-binding motif protein-15 gene. This translocation has been associated with acute megakaryocytic leukemia. [provided by RefSeq, July 2008]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: AB037859.2, AJ297258.1 [ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025081, ERS025082 [ECO:0000350] MRPL42 exonic 28977 39S ribosomal Mammalian mitochondrial ribosomal proteins are encoded by 90 protein L42, nuclear genes and help in protein synthesis within the mitochondrial mitochondrion. Mitochondrial ribosomes (mitoribosomes) precursor consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a protein identified as belonging to both the 28S and the 39S subunits. Alternative splicing results in multiple transcript variants. Pseudogenes corresponding to this gene are found on chromosomes 4q, 6p, 6q, 7p, and 15q. [provided by RefSeq, May 2011]. Transcript Variant: This variant (1) encodes the supported protein. Both variants 1 and 2 encode the same protein. Sequence Note: This RefSeq record was created from transcript and genomic sequence data to make the sequence consistent with the reference genome assembly. The genomic coordinates used for the transcript record were based on transcript alignments. ##RefSeq-Attributes-START## gene product(s) localized to mito. :: reported by MitoCarta ##RefSeq-Attributes-END## Transcript exon combination :: AK000285.1, AF151038.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025082 [ECO:0000348] MTHFD1 exonic 4522 C-1- This gene encodes a protein that possesses three distinct 91 tetrahydrofolate enzymatic activities, 5,10-methylenetetrahydrofolate synthase, dehydrogenase, 5,10-methenyltetrahydrofolate cytoplasmic cyclohydrolase and 10-formyltetrahydrofolate synthetase. Each of these activities catalyzes one of three sequential reactions in the interconversion of 1-carbon derivatives of tetrahydrofolate, which are substrates for methionine, thymidylate, and de novo purine syntheses. The trifunctional enzymatic activities are conferred by two major domains, an aminoterminal portion containing the dehydrogenase and cyclohydrolase activities and a larger synthetase domain. [provided by RefSeq, July 2008]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. ##RefSeq-Attributes-START## CDS uses downstream in-frame AUG :: experimental evidence (PMID:3053686) ##RefSeq-Attributes-END## Transcript exon combination :: BC050420.1, J04031.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025082 [ECO:0000348] NFIL3 exonic 4783 nuclear factor Expression of interleukin-3 (IL3; MIM 147740) is restricted 92 interleukin-3- to activated T cells, natural killer (NK) cells, and mast cell regulated lines. Transcription initiation depends on the activating protein capacity of specific protein factors, such as NFIL3, that bind to regulatory regions of the gene, usually upstream of the transcription start site (Zhang et al., 1995 [PubMed 7565758]). [supplied by OMIM, February 2009]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: S79880.1, U26173.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025082 [ECO:0000348] NLRP12 exonic 91662 NACHT, LRR This gene encodes a member of the CATERPILLER family 93 and PYD of cytoplasmic proteins. The encoded protein, which contains domains- an N-terminal pyrin domain, a NACHT domain, a NACHT- containing associated domain, and a C-terminus leucine-rich repeat protein 12 region, functions as an attenuating factor of inflammation by isoform 2 suppressing inflammatory responses in activated monocytes. Mutations in this gene cause familial cold autoinflammatory syndrome type 2. Alternative splicing results in multiple transcript variants. [provided by RefSeq, March 2013]. Transcript Variant: This variant (2) uses an alternate splice site in the central coding region, compared to variant 3, resulting in an isoform (2) that is 1 aa shorter than isoform 3. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: AY095146.1, BC028069.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025089 [ECO:0000348] NQO2 exonic 4835 ribosyldihydro- NQO2 (EC 1.10.99.2) is a flavoprotein that catalyzes the 2- 94 nicotinamide electron reduction of various quinones, redox dyes, and the dehydrogenase vitamin K menadione. NQO2 predominantly uses [quinone] dihydronicotinamide riboside (NRH) as the electron donor (summary by Wu et al., 1997 [PubMed 9367528]). [supplied by OMIM, July 2010]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: J02888.1, AK311746.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025082 [ECO:0000348] NRIP1 exonic 8204 nuclear Nuclear receptor interacting protein 1 (NRIP1) is a nuclear 95 receptor- protein that specifically interacts with the hormone-dependent interacting activation domain AF2 of nuclear receptors. Also known as protein 1 RIP140, this protein modulates transcriptional activity of the estrogen receptor. [provided by RefSeq, July 2008]. Sequence Note: The RefSeq transcript and protein were derived from transcript and genomic sequence to make the sequence consistent with the reference genome assembly. The extent of this RefSeq transcript is supported by transcript alignments. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: AK289786.1, DA230125.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025098 [ECO:0000348] NUDT4 exonic 11163 diphosphoinositol The protein encoded by this gene regulates the turnover of 96 polyphosphate diphosphoinositol polyphosphates. The turnover of these phosphohydrolase high-energy diphosphoinositol polyphosphates represents a 2 isoform molecular switching activity with important regulatory alpha consequences. Molecular switching by diphosphoinositol polyphosphates may contribute to regulating intracellular trafficking. Several alternatively spliced transcript variants have been described, but the full-length nature of some variants has not been determined. Isoforms DIPP2alpha and DIPP2beta are distinguishable from each other solely by DIPP2beta possessing one additional amino acid due to intron boundary skidding in alternate splicing. [provided by RefSeq, July 2008]. Transcript Variant: This variant (1) encodes the predominant isoform (alpha). Transcript exon combination :: AF191651.1, AF191650.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025082 [ECO:0000348] NUDT4P1 exonic 440672 N/A N/A 97 OVOL2 exonic 58495 transcription N/A 98 factor Ovo- like 2 PDE3B intronic 5140 cGMP- N/A 99 inhibited 3′,5′- cyclic phosphodiesterase B PDGFRA exonic 5156 platelet- This gene encodes a cell surface tyrosine kinase receptor for 100 derived members of the platelet-derived growth factor family. These growth factor growth factors are mitogens for cells of mesenchymal origin. receptor alpha The identity of the growth factor bound to a receptor precursor monomer determines whether the functional receptor is a homodimer or a heterodimer, composed of both platelet- derived growth factor receptor alpha and beta polypeptides. Studies suggest that this gene plays a role in organ development, wound healing, and tumor progression. Mutations in this gene have been associated with idiopathic hypereosinophilic syndrome, somatic and familial gastrointestinal stromal tumors, and a variety of other cancers. [provided by RefSeq, March 2012]. Sequence Note: This RefSeq record was created from transcript and genomic sequence data because no single transcript was available for the full length of the gene. The extent of this transcript is supported by transcript alignments and orthologous data. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: M21574.1, M22734.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025084 [ECO:0000348] PDSS2 exonic 57107 decaprenyl- The protein encoded by this gene is an enzyme that 101 diphosphate synthesizes the prenyl side-chain of coenzyme Q, or synthase ubiquinone, one of the key elements in the respiratory chain. subunit 2 The gene product catalyzes the formation of all trans- polyprenyl pyrophosphates from isopentyl diphosphate in the assembly of polyisoprenoid side chains, the first step in coenzyme Q biosynthesis. Defects in this gene are a cause of coenzyme Q10 deficiency. [provided by RefSeq, October 2009]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: BC039906.1, AF254956.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025084, ERS025088 [ECO:0000348] PHACTR4 exonic 65979 phosphatase This gene encodes a member of the phosphatase and actin 102 and actin regulator (PHACTR) family. Other PHACTR family regulator 4 members have been shown to inhibit protein phosphatase 1 isoform 1 (PP1) activity, and the homolog of this gene in the mouse has been shown to interact with actin and PP1. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, July 2008]. Transcript Variant: This variant (1) represents the longer transcript but encodes the shorter isoform (1). Sequence Note: This RefSeq record was created from transcript and genomic sequence data to make the sequence consistent with the reference genome assembly. The genomic coordinates used for the transcript record were based on transcript alignments. Transcript exon combination :: CR749449.1, BC029266.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025084, ERS025087 [ECO:0000348] PIAS2 exonic 9063 E3 SUMO- This gene encodes a member of the protein inhibitor of 103 protein ligase activated STAT (PIAS) family. PIAS proteins function as PIAS2 SUMO E3 ligases and play important roles in many cellular isoform alpha. processes by mediating the sumoylation of target proteins. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. Isoforms of the encoded protein enhance the sumoylation of specific target proteins including the p53 tumor suppressor protein, c-Jun, and the androgen receptor. A pseudogene of this gene is located on the short arm of chromosome 4. The symbol MIZ1 has also been associated with ZBTB17 which is a different gene located on chromosome 1. [provided by RefSeq, August 2011]. Transcpipt Variant: This variant (alpha) utilizes an alternate 3′ coding exon, compared to variant beta, resulting in a shorter isoform (alpha) that has a unique C-terminus compared to isoform beta. Sequence Note: This RefSeq record was created from transcript and genomic sequence data to make the sequence consistent with the reference genome assembly. The genomic coordinates used for the transcript record were based on transcript alignments. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: BC015190.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025088 [ECO:0000348] PIK3CD exonic 5293 phosphatidylinositol Phosphoinositide 3-kinases (PI3Ks) phosphorylate inositol 104 4,5- lipids and are involved in the immune response. The protein bisphosphate encoded by this gene is a class I PI3K found primarily in 3-kinase leukocytes. Like other class I PI3Ks (p110-alpha p110-beta, catalytic and p110-gamma), the encoded protein binds p85 adapter subunit delta proteins and GTP-bound RAS. However, unlike the other isoform class I PI3Ks, this protein phosphorylates itself, not p85 protein. [provided by RefSeq, July 2010]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: U86453.1, Y10055.2 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025089 [ECO:0000348] PKHD1 intronic 5314 fibrocystin The protein encoded by this gene is predicted to have a single 105 isoform 1 transmembrane (TM)-spanning domain and multiple copies of precursor an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, July 2008]. Transcript Variant: This variant (1) encodes the longer isoform of this protein. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: AY074797.1, AF480064.1 [ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025084, ERS025085 [ECO:0000350] PLXNC1 exonic 10154 Plexin C1 This gene encodes a member of the plexin family. Plexins are 106 transmembrane receptors for semaphorins, a large family of proteins that regulate axon guidance, cell motility and migration, and the immune response. The encoded protein and its ligand regulate melanocyte adhesion, and viral semaphorins may modulate the immune response by binding to this receptor. The encoded protein may be a tumor suppressor protein for melanoma. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, January 2011]. Transcript Variant: This variant (2) lacks multiple 5′ exons but contains an alternate 5′ exon, compared to variant 1. This variant is represented as non- coding due to the presence of an upstream ORF that is predicted to interfere with translation of the longest in-frame ORF. Translation of the upstream ORF renders the transcript a candidate for nonsense-mediated mRNA decay (NMD). Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. RNAseq introns :: single sample supports all introns ERS025084, ERS025088 [ECO:0000348] PNPLA4 exonic 8228 patatin-like This gene encodes a member of the patatin-like family of 107 phospholipase phospholipases. The encoded enzyme has both triacylglycerol domain- lipase and transacylase activities and may be involved in containing adipocyte triglyceride homeostasis. Alternate splicing results protein 4 in multiple transcript variants. A pseudogene of this gene is isoform 1 found on chromosome Y. [provided by RefSeq, February 2010]. precursor Transcript Variant: This variant (1) represents the longest transcript and encodes the longer isoform (1). Variants 1 and 2 encode the same isoform (1). Sequence Note: The RefSeq transcript and protein were derived from transcript and genomic sequence to make the sequence consistent with the reference genome assembly. The extent of this transcript is supported by transcript alignments. Transcript exon combination :: U03886.1, AK289888.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025091, ERS025098 [ECO:0000348] PNPT1 both 87178 polyribonucleotide The protein encoded by this gene belongs to the evolutionary 108 nucleotidyl- conserved polynucleotide phosphorylase family comprised of transferase 1, phosphate dependent 3′-to-5′ exoribonucleases implicated in mitochondrial RNA processing and degradation. This enzyme is precursor predominantly localized in the mitochondrial intermembrane space and is involved in import of RNA to mitochondria. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency-13 and autosomal recessive nonsyndromic deafness-70. Related pseudogenes are found on chromosomes 3 and 7. [provided by RefSeq, December 2012]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: BC053660.1, AJ458465.1 [ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025081, ERS025082 [ECO:0000350] ##RefSeq- Attributes-START## gene product(s) localized to mito. :: PMID: 12798676; reported by MitoCarta ##RefSeq- Attributes-END## PPP2R3B intronic 28227 serine/threonine- Protein phosphatase 2 (formerly named type 2A) is one of the 109 protein four major Ser/Thr phosphatases and is implicated in the phosphatase negative control of cell growth and division. Protein 2A regulatory phosphatase 2 holoenzymes are heterotrimeric proteins subunit B″ composed of a structural subunit A, a catalytic subunit C, and subunit beta a regulatory subunit B. The regulatory subunit is encoded by a diverse set of genes that have been grouped into the B/PR55, B′/PR61, and B″/PR72 families. These different regulatory subunits confer distinct enzymatic specificities and intracellular localizations to the holozenzyme. The product of this gene belongs to the B″ family. The B″ family has been further divided into subfamilies. The product of this gene belongs to the beta subfamily of regulatory subunit B″. [provided by RefSeq, April 2010]. Sequence Note: This RefSeq record was created from transcript and genomic sequence data to make the sequence consistent with the reference genome assembly. The genomic coordinates used for the transcript record were based on transcript alignments. Transcript exon combination :: BK000521.1, BC063429.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025084 [ECO:0000348] PRKCB both 5579 protein kinase Protein kinase C (PKC) is a family of serine- and threonine- 110 C beta type specific protein kinases that can be activated by calcium and isoform 1 second messenger diacylglycerol. PKC family members phosphorylate a wide variety of protein targets and are known to be involved in diverse cellular signaling pathways. PKC family members also serve as major receptors for phorbol esters, a class of tumor promoters. Each member of the PKC family has a specific expression profile and is believed to play a distinct role in cells. The protein encoded by this gene is one of the PKC family members. This protein kinase has been reported to be involved in many different cellular functions, such as B cell activation, apoptosis induction, endothelial cell proliferation, and intestinal sugar absorption. Studies in mice also suggest that this kinase may also regulate neuronal functions and correlate fear-induced conflict behavior after stress. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, July 2008]. Transcript Variant: This variant (1) uses an alternate splice junction at the 5′ end of the last exon compared to variant 2. The resulting isoform (1) has a distinct and shorter C-terminus compared to isoform 2. Sequence Note: This RefSeq record was created from transcript and genomic sequence data because no single transcript was available for the full length of the gene. The extent of this transcript is supported by transcript alignments. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: X06318.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025082, ERS025084 [ECO:0000348] PRKCH intronic 5583 protein kinase Protein kinase C (PKC) is a family of serine- and threonine- 111 C eta type specific protein kinases that can be activated by calcium and the second messenger diacylglycerol. PKC family members phosphorylate a wide variety of protein targets and are known to be involved in diverse cellular signaling pathways. PKC family members also serve as major receptors for phorbol esters, a class of tumor promoters. Each member of the PKC family has a specific expression profile and is believed to play a distinct role in cells. The protein encoded by this gene is one of the PKC family members. It is a calcium-independent and phospholipids-dependent protein kinase. It is predominantly expressed in epithelial tissues and has been shown to reside specifically in the cell nucleus. This protein kinase can regulate keratinocyte differentiation by activating the MAP kinase MAPK13 (p38delta)-activated protein kinase cascade that targets CCAAT/enhancer-binding protein alpha (CEBPA). It is also found to mediate the transcription activation of the transglutaminase 1 (TGM1) gene. [provided by RefSeq, July 2008]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: BC037268.1, AK290183.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025083 [ECO:0000348] PSTPIP1 exonic 9051 proline-serine- The protein encoded by this gene binds to the cytoplasmic tail 112 threonine of CD2, an effector of T cell activation and adhesion, phosphatase- negatively affecting CD2-triggered T cell activation. The interacting encoded protein appears to be a scaffold protein and a protein 1 regulator of the actin cytoskeleton. It has also been shown to bind ABL1, PTPN18, WAS, CD2AP, and PTPN12. Mutations in this gene are a cause of PAPA syndrome. [provided by RefSeq, July 2008]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: BC008602.1, U94778.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025084, ERS025088 [ECO:0000348] PTPN2 exonic 5771 tyrosine- The protein encoded by this gene is a member of the protein 113 protein tyrosine phosphatase (PTP) family. Members of the PTP phosphatase family share a highly conserved catalytic motif, which is non-receptor essential for the catalytic activity. PTPs are known to be type 2 isoform signaling molecules that regulate a variety of cellular 1 processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. Epidermal growth factor receptor and the adaptor protein Shc were reported to be substrates of this PTP, which suggested the roles in growth factor mediated cell signaling. Multiple alternatively spliced transcript variants encoding different isoforms have been found. Two highly related but distinctly processed pseudogenes that localize to chromosomes 1 and 13, respectively, have been reported. [provided by RefSeq, May 2011]. Transcript Variant: This variant (1) encodes the longest isoform (1). Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: M25393.1, AK292570.1 [ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025081, ERS025082 [ECO:0000350] PTPRN2 intronic 5799 receptor-type The protein encoded by this gene is a member of the protein 114 tyrosine- tyrosine phosphatase (PTP) family. PTPs are known to be protein signaling molecules that regulate a variety of cellular phosphatase processes including cell growth, differentiation, mitotic cycle, N2 isoform 1 and oncogenic transformation. This PTP possesses an precursor extracellular region, a single transmembrane region, and a single intracellular catalytic domain, and thus represents a receptor-type PTP. The catalytic domain of this PTP is most closely related to PTPRN/IA-2beta. This PTP and PTPRN are both found to be major autoantigens associated with insulin- dependent diabetes mellitus. Three alternatively spliced transcript variants of this gene, which encode distinct proteins, have been reported. [provided by RefSeq, July 2008]. Transcript Variant: This variant (1) encodes the longest isoform (1). Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: U66702.1, AF007555.1 [ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025081, ERS025082 [ECO:0000350] RAB37 exonic 326624 ras-related Rab proteins are low molecular mass GTPases that are critical 115 protein Rab- regulators of vesicle trafficking. For additional background 37 isoform 2 information on Rab proteins, see MIM 179508. [supplied by OMIM, April 2006]. Transcript Variant: This variant (2) represents use of an alternate promoter, 5′ UTR, and alternate start codon, and includes an alternate coding exon, compared to variant 3. The resulting isoform (2) has a distinct and longer N-terminus, compared to isoform 3. Transcript exon combination :: AK098068.1, BX332255.2 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025084, ERS025088 [ECO:0000348] RBFOX1 intronic 54715 RNA binding The Fox-1 family of RNA-binding proteins is evolutionarily 116 protein fox-1 conserved, and regulates tissue-specific alternative splicing in homolog 1 metazoa. Fox-1 recognizes a (U)GCAUG stretch in regulated isoform 1 exons or in flanking introns. The protein binds to the C- terminus of ataxin-2 and may contribute to the restricted pathology of spinocerebellar ataxia type 2 (SCA2). Ataxin-2 is the product of the SCA2 gene which causes familial neurodegenerative diseases. Fox-1 and ataxin-2 are both localized in the trans-Golgi network. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, November 2011]. Transcript Variant: This variant (1), also known as gamma, encodes the longest isoform (1). Sequence Note: This RefSeq record was created from transcript and genomic sequence data because no single transcript was available for the full length of the gene. The extent of this transcript is supported by transcript alignments. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: AF229057.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025083, ERS025099 [ECO:0000348] RCC1 exonic 1104 N/A N/A 117 RGCC exonic 28984 regulator of This gene is thought to regulate cell cycle progression. It is 118 cell cycle induced by p53 in response to DNA damage, or by sublytic RGCC levels of complement system proteins that result in activation of the cell cycle. The encoded protein localizes to the cytoplasm during interphase and to centrosomes during mitosis. The protein forms a complex with polo-like kinase 1. The protein also translocates to the nucleus in response to treatment with complement system proteins, and can associate with and increase the kinase activity of cell division cycle 2 protein. In different assays and cell types, overexpression of this protein has been shown to activate or suppress cell cycle progression. [provided by RefSeq, July 2008]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: BC066334.1, BG037019.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025092 [ECO:0000348] RHOQ intronic 23433 rho-related This gene encodes a member of the Rho family of small 119 GTP-binding GTPases, which cycle between inactive GDP-bound and protein RhoQ active GTP-bound states and function as molecular switches precursor in signal transduction cascades. Rho proteins promote reorganization of the actin cytoskeleton and regulate cell shape, attachment, and motility. The encoded protein is an important signalling protein for sarcomere assembly and has been shown to play a significant role in the exocytosis of the solute carrier family 2, facilitated glucose transporter member 4 and other proteins, possibly acting as the signal that turns on the membrane fusion machinery. Three related pseudogene have been identified on chromosomes 2 and 14. [provided by RefSeq, August 2011]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: BX428852.2, BC013135.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025082 [ECO:0000348] RNASE3 exonic 6037 eosinophil N/A 120 cationic protein precursor RNASE10 exonic 338879 inactive N/A 121 ribonuclease- like protein 10 precursor RPL38 exonic 6169 60S ribosomal Ribosomes, the organelles that catalyze protein synthesis, 122 protein L38 consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 60S subunit. The protein belongs to the L38E family of ribosomal proteins. It is located in the cytoplasm. Alternative splice variants have been identified, both encoding the same protein. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome, including one located in the promoter region of the type 1 angiotensin II receptor gene. [provided by RefSeq, July 2008]. Transcript Variant: This variant (1) is the longer and predominant transcript. Variants 1 and 2 encode the same protein. Transcript exon combination :: BQ276548.1, BU569438.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025082 [ECO:0000348] RPTOR intronic 57521 regulatory- This gene encodes a component of a signaling pathway that 123 associated regulates cell growth in response to nutrient and insulin protein of levels. The encoded protein forms a stoichiometric complex mTOR with the mTOR kinase, and also associates with eukaryotic isoform 1 initiation factor 4E-binding protein-1 and ribosomal protein S6 kinase. The protein positively regulates the downstream effector ribosomal protein S6 kinase, and negatively regulates the mTOR kinase. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, September 2009]. Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (1). Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: AY090663.1, BC136652.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025083, ERS025085 [ECO:0000348] SERPINB4 exonic 6318 serpin B4 N/A 124 SERPINB6 exonic 5269 serpin B6 The protein encoded by this gene is a member of the serpin 125 isoform a (serine proteinase inhibitor) superfamily, and ovalbumin(ov)- serpin subfamily. It was originally discovered as a placental thrombin inhibitor. The mouse homolog was found to be expressed in the hair cells of the inner ear. Mutations in this gene are associated with nonsyndromic progressive hearing loss, suggesting that this serpin plays an important role in the inner ear in the protection against leakage of lysosomal content during stress, and that loss of this protection results in cell death and sensorineural hearing loss. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, September 2010]. Transcript Variant: This variant (1) represents the predominant transcript. Variants 1, 5 and 6 encode the same isoform (a). Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: AK314578.1, BC098564.1 [ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025081, ERS025082 [ECO:0000350] SLC3A2 both 6520 4F2 cell- This gene is a member of the solute carrier family and 126 surface encodes a cell surface, transmembrane protein. The protein antigen heavy exists as the heavy chain of a heterodimer, covalently bound chain isoform through di-sulfide bonds to one of several possible light b chains. The encoded transporter plays a role in regulation of intracellular calcium levels and transports L-type amino acids. Alternatively spliced transcript variants, encoding different isoforms, have been characterized. [provided by RefSeq, November 2010]. Transcript Variant: This variant (2) represents the longest transcript and encodes the longest isoform (b). Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: AK025584.1 [ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025082, ERS025084 [ECO:0000350] SLC17A5 both 26503 sialin This gene encodes a membrane transporter that exports free 127 sialic acids that have been cleaved off of cell surface lipids and proteins from lysosomes. Mutations in this gene cause sialic acid storage diseases, including infantile sialic acid storage disorder and and Salla disease, an adult form. [provided by RefSeq, July 2008]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: BC020961.2, AJ387747.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025082 [ECO:0000348] SNHG3 exonic 8420 N/A N/A 128 SNORD17 exonic 692086 N/A N/A 129 SNX5 exonic 27131 sorting nexin- This gene encodes a member of the sorting nexin family. 130 5 isoform a Members of this family contain a phox (PX) domain, which is a phosphoinositide binding domain, and are involved in intracellular trafficking. This protein functions in endosomal sorting, the phosphoinositide-signaling pathway, and macropinocytosis. This gene may play a role in the tumorigenesis of papillary thyroid carcinoma. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, September 2013]. Transcript Variant: This variant (1) differs in the 5′ UTR, compared to variant 2. Variants 1 and 2 encode the same protein (isoform a). Transcript exon combination :: BC000100.3, AF121855.1 [ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025081, ERS025082 [ECO:0000350] SOCS2 exonic 8835 suppressor of This gene encodes a member of the suppressor of cytokine 131 cytokine signaling (SOCS) family. SOCS family members are signaling 2 cytokine-inducible negative regulators of cytokine receptor signaling via the Janus kinase/signal transducer and activation of transcription pathway (the JAK/STAT pathway). SOCS family proteins interact with major molecules of signaling complexes to block further signal transduction, in part, by proteasomal depletion of receptors or signal-transducing proteins via ubiquitination. The expression of this gene can be induced by a subset of cytokines, including erythropoietin, GM-CSF, IL10, interferon (IFN)-gamma and by cytokine receptors such as growth horomone receptor. The protein encoded by this gene interacts with the cytoplasmic domain of insulin-like growth factor-1 receptor (IGF1R) and is thought to be involved in the regulation of IGF1R mediated cell signaling. This gene has pseudogenes on chromosomes 20 and 22. Alternative splicing results in multiple transcript variants. [provided by RefSeq, July 2012]. Transcript Variant: This variant (1) differs in the 5′ UTR, compared to variant 5. Variants 1-6 encode the same protein. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: AK313165.1, AL522912.3 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025082 [ECO:0000348] SOCS2- exonic 144481 N/A N/A 132 AS1 ST8SIA5 exonic 29906 alpha-2,8- The protein encoded by this gene is a type II membrane 133 sialyltransferase protein that may be present in the Golgi apparatus. The 8E encoded protein, which is a member of glycosyltransferase family 29, may be involved in the synthesis of gangliosides GD1c, GT1a, GQ1b, and GT3 from GD1a, GT1b, GM1b, and GD3, respectively. [provided by RefSeq, July 2008]. Transcript exon combination :: AK056270.1, BC108910.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025082, ERS025084 [ECO:0000348] STIM2 intronic 57620 stromal This gene is a member of the stromal interaction molecule 134 interaction (STIM) family and likely arose, along with related family molecule 2 member STIM1, from a common ancestral gene. The encoded isoform 1 protein functions to regulate calcium concentrations in the precursor cytosol and endoplasmic reticulum, and is involved in the activation of plasma membrane Orai Ca(2+) entry channels. This gene initiates translation from a non-AUG (UUG) start site. A signal peptide is cleaved from the resulting protein. Multiple transcript variants result from alternative splicing. [provided by RefSeq, December 2009]. Transcript Variant: This variant (1) encodes the longest isoform (1). Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: BC136449.1, AK096846.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025084 [ECO:0000348] ##RefSeq-Attributes-START## CDS uses downstream in-frame AUG :: experimental evidence (PMID:11463338) non-AUG initiation codon :: PMID: 11463338 ##RefSeq-Attributes-END## TBC1D16 intronic 125058 TBC1 domain N/A 136 family member 16 isoform a TEX29 exonic 121793 testis- N/A 137 expressed sequence 29 protein TNFRSF10A exonic 8797 tumor necrosis The protein encoded by this gene is a member of the TNF- 138 factor receptor receptor superfamily. This receptor is activated by tumor superfamily necrosis factor-related apoptosis inducing ligand member 10A (TNFSF10/TRAIL), and thus transduces cell death signal and induces cell apoptosis. Studies with FADD-deficient mice suggested that FADD, a death domain containing adaptor protein, is required for the apoptosis mediated by this protein. [provided by RefSeq, July 2008]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: BC012866.1, AK291299.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025081, ERS025084 [ECO:0000348] TNFRSF13C exonic 115650 tumor necrosis B cell-activating factor (BAFF) enhances B-cell survival in 139 factor receptor vitro and is a regulator of the peripheral B-cell population. superfamily Overexpression of Baff in mice results in mature B-cell member 13C hyperplasia and symptoms of systemic lupus erythematosus (SLE). Also, some SLE patients have increased levels of BAFF in serum. Therefore, it has been proposed that abnormally high levels of BAFF may contribute to the pathogenesis of autoimmune diseases by enhancing the survival of autoreactive B cells. The protein encoded by this gene is a receptor for BAFF and is a type III transmembrane protein containing a single extracellular cysteine-rich domain. It is thought that this receptor is the principal receptor required for BAFF-mediated mature B-cell survival. [provided by RefSeq, July 2008]. Sequence Note: The RefSeq transcript and protein were derived from genomic sequence to make the sequence consistent with the reference genome assembly. The genomic coordinates used for the transcript record were based on alignments. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: AF373846.1, BC112030.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025089 [ECO:0000348] TNFRSF18 exonic 8784 tumor necrosis This gene encodes a member of the TNF-receptor 140 factor receptor superfamily. The encoded receptor has been shown to have superfamily increased expression upon T-cell activation, and it is thought member 18 to play a key role in dominant immunological self-tolerance isoform 1 maintained by CD25(+)CD4(+) regulatory T cells. Knockout precursor studies in mice also suggest the role of this receptor is in the regulation of CD3-driven T-cell activation and programmed cell death. Three alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, February 2011]. Transcript Variant: This variant (1) represents the longest transcript. It contains an extra coding segment, which leads to a frame shift, compared to variant 2. The resulting preotein (isoform 1) contains a distinct and shorter C-terminus, as compared to isoform 2. Sequence Note: This RefSeq record was created from transcript and genomic sequence data to make the sequence consistent with the reference genome assembly. The genomic coordinates used for the transcript record were based on transcript alignments. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: AY358877.1, AF125304.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025089, ERS025093 [ECO:0000348] TRAFD1 exonic 10906 TRAF-type The innate immune system confers host defense against viral 141 zinc finger and microbial infection, and TRAFD1 is a negative feedback domain- regulator that controls excessive immune responses (Sanada containing et al., 2008 [PubMed 18849341]). [supplied by OMIM, December protein 1 2009]. Transcript Variant: This variant (1) represents the longer transcript. Variants 1 and 2 both encode the same protein. Transcript exon combination :: AK122620.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025083, ERS025084 [ECO:0000348] TRPM2 exonic 7226 Transient The protein encoded by this gene is a calcium-permeable 142 Receptor cation channel that is regulated by free intracellular ADP- Potential ribose. The encoded protein is activated by oxidative stress Cation and confers susceptibility to cell death. Several alternatively Channel spliced transcript variants of this gene have been described, Subfamily M but their full-length nature is not known. [provided by Member 2 RefSeq, July 2008]. Transcript Variant: This variant (2) uses an alternate in-frame splice junction at the 5′ end of an exon compared to variant 1. This results in the introduction of a premature stop codon and renders the transcript a nonsense- mediated mRNA decay (NMD) candidate. Therefore, this transcript is not thought to be protein-coding. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. RNAseq introns :: mixed/partial sample support ERS025081, ERS025082 [ECO:0000350] TTLL10 exonic 254173 inactive N/A 143 polyglycylase TTLL10 isoform 1 TTYH2 exonic 94015 protein tweety This gene encodes a member of the tweety family of proteins. 144 homolog 2 Members of this family function as chloride anion channels. isoform 1 The encoded protein functions as a calcium(2+)-activated large conductance chloride(−) channel, and may play a role in kidney tumorigenesis. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, July 2008]. Transcript Variant: This variant (1) represents the longer transcript, and encodes the longer isoform (1). Transcript exon combination :: AF319952.1, BC107492.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025082, ERS025083 [ECO:0000348] UBE2N exonic 7334 ubiquitin- The modification of proteins with ubiquitin is an important 145 conjugating cellular mechanism for targeting abnormal or short-lived enzyme E2 N proteins for degradation. Ubiquitination involves at least three classes of enzymes: ubiquitin-activating enzymes, or E1s, ubiquitin-conjugating enzymes, or E2s, and ubiquitin-protein ligases, or E3s. This gene encodes a member of the E2 ubiquitin-conjugating enzyme family. Studies in mouse suggest that this protein plays a role in DNA postreplication repair. [provided by RefSeq, July 2008]. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination :: BC000396.2, D83004.1 [ECO:0000332] RNAseq introns :: single sample supports all introns ERS025084 [ECO:0000348] VCX exonic 26609 variable This gene belongs to the VCX/Y gene family, which has 146 charge X- multiple members on both X and Y chromosomes, and all are linked protein expressed exclusively in male germ cells. The X-linked 1 members are clustered on chromosome Xp22 and Y-linked members are two identical copies of the gene within a palindromic region on Yq11. The family members share a high degree of sequence identity, with the exception that a 30- bp unit is tandemly repeated in X-linked members but occurs only once in Y-linked members. The VCX gene cluster is polymorphic in terms of copy number; different individuals may have a different number of VCX genes. VCX/Y genes encode small and highly charged proteins of unknown function. The presence of a putative bipartite nuclear localization signal suggests that VCX/Y members are nuclear proteins. This gene contains 10 repeats of the 30-bp unit. [provided by RefSeq, July 2008]. Transcript exon combination :: AF167081.2 [ECO:0000332] VSTM1 intronic 284415 V-set and N/A 147 transmembrane domain- containing protein 1 precursor VWA2 exonic 340706 von This gene encodes a member of the von Willebrand factor A- 148 Willebrand like domain protein superfamily. The encoded protein is factor A localized to the extracellular matrix and may serve as a domain- structural component in basement membranes or in anchoring containing structures on scaffolds of collagen VII or fibrillin. This gene protein 2 has been linked to type 1A diabetes and is a candidate precursor serological marker for colon cancer. [provided by RefSeq, January 2013]. Sequence Note: This RefSeq record was created from transcript and genomic sequence data to make the sequence consistent with the reference genome assembly. The genomic coordinates used for the transcript record were based on transcript alignments. CCDS Note: The coding region has been updated to represent an alternative 3′ splicing pattern that is more supported by the available transcript and protein data. Transcript exon combination :: AY572972.1, AJ536328.2 [ECO:0000332] RNAseq introns :: mixed/partial sample support ERS025081, ERS025084 [ECO:0000350] ZNF350 exonic 59348 zinc finger N/A 149 protein 350 ZNF432 exonic 9668 zinc finger N/A 150 protein 432 ZNF577 exonic 84765 N/A N/A 151 ZNF613 exonic 79898 zinc finger N/A 152 protein 613 isoform 1 ZNF614 exonic 80110 zinc finger N/A 153 protein 614 ZNF615 exonic 284370 zinc finger N/A 154 protein 615 isoform 1 ZNF649 exonic 65251 zinc finger N/A 155 protein 649 ZNF841 exonic 284371 zinc finger N/A 156 protein 841

For all genes listed in Table 2 (namely, those relevant to CNV-subregions of interest), Table 3 represents a non-redundant list.

TABLE 4 A non-redundant list of transcript variants that correspond to the genes in Table 3 RefSeq RefSeq Gene Exon Accession SEQ Symbol overlap Number mRNA Description ID MIR200B exonic NR 029639 Homo sapiens microRNA 200b (MIR200B), microRNA. 173 MIR200A exonic NR 029834 Homo sapiens microRNA 200a (MIR200A), microRNA. 174 MIR429 exonic NR 029957 Homo sapiens microRNA 429 (MIR429), microRNA. 175 TTLL10 exonic NM 001130045 Homo sapiens tubulin tyrosine ligase-like family, member 10 176 (TTLL10), transcript variant 1, mRNA. TTLL10 exonic NM 153254 Homo sapiens tubulin tyrosine ligase-like family, member 10 177 (TTLL10), transcript variant 2, mRNA. TNFRSF18 exonic NM 004195 Homo sapiens tumor necrosis factor receptor superfamily, member 178 18 (TNFRSF18), transcript variant 1, mRNA. TNFRSF18 exonic NM 148901 Homo sapiens tumor necrosis factor receptor superfamily, member 179 18 (TNFRSF18), transcript variant 2, mRNA. TNFRSF18 exonic NM 148902 Homo sapiens tumor necrosis factor receptor superfamily, member 180 18 (TNFRSF18), transcript variant 3, mRNA. PIK3CD exonic NM 005026 Homo sapiens phosphatidylinositol-4,5-bisphosphate 3-kinase, 181 catalytic subunit delta (PIK3CD), mRNA. CAPZB intronic NR 038125 Homo sapiens capping protein (actin filament) muscle Z-line, beta 182 (CAPZB), transcript variant 4, non-coding RNA. CAPZB intronic NM 001206540 Homo sapiens capping protein (actin filament) muscle Z-line, beta 183 (CAPZB), transcript variant 2, mRNA. CAPZB intronic NM 004930 Homo sapiens capping protein (actin filament) muscle Z-line, beta 184 (CAPZB), transcript variant 1, mRNA. IFNLR1 exonic NM 170743 Homo sapiens interferon, lambda receptor 1 (IFNLR1), transcript 185 variant 1, mRNA. IFNLR1 exonic NM 173064 Homo sapiens interferon, lambda receptor 1 (IFNLR1), transcript 186 variant 2, mRNA. IFNLR1 exonic NM 173065 Homo sapiens interferon, lambda receptor 1 (IFNLR1), transcript 187 variant 3, mRNA. PHACTR4 exonic NM 001048183 Homo sapiens phosphatase and actin regulator 4 (PHACTR4), 189 transcript variant 1, mRNA. PHACTR4 exonic NM 023923 Homo sapiens phosphatase and actin regulator 4 (PHACTR4), 190 transcript variant 2, mRNA. SNHG3 exonic NR 002909 Homo sapiens small nucleolar RNA host gene 3 (non-protein 191 coding) (SNHG3), transcript variant 2, non-coding RNA. SNHG3 exonic NR 036473 Homo sapiens small nucleolar RNA host gene 3 (non-protein coding) (SNHG3), transcript variant 1, non-coding RNA. RCC1 exonic NM 001048199 Homo sapiens regulator of chromosome condensation 1 (RCC1), 192 transcript variant 4, mRNA. RCC1 exonic NR 030725 Homo sapiens regulator of chromosome condensation 1 (RCC1), 193 transcript variant 5, non-coding RNA. RCC1 exonic NR 030726 Homo sapiens regulator of chromosome condensation 1 (RCC1), 194 transcript variant 6, non-coding RNA. RCC1 exonic NM 001048194 Homo sapiens regulator of chromosome condensation 1 (RCC1), 195 transcript variant 1, mRNA. RCC1 exonic NM 001048195 Homo sapiens regulator of chromosome condensation 1 (RCC1), 196 transcript variant 2, mRNA. RCC1 exonic NM 001269 Homo sapiens regulator of chromosome condensation 1 (RCC1), 197 transcript variant 3, mRNA. AGBL4 intronic NM 032785 Homo sapiens ATP/GTP binding protein-like 4 (AGBL4), mRNA. 198 GPATCH2 intronic NM 018040 Homo sapiens G patch domain containing 2 (GPATCH2), mRNA. 199 RHOQ intronic NM 012249 Homo sapiens ras homolog family member Q (RHOQ), mRNA. 200 PNPT1 both NM 033109 Homo sapiens polyribonucleotide nucleotidyltransferase 1 201 (PNPT1), mRNA. MCEE both NM 032601 Homo sapiens methylmalonyl CoA epimerase (MCEE), mRNA. 202 HK2 exonic NM 000189 Homo sapiens hexokinase 2 (HK2), mRNA. 203 FHL2 exonic NM 201557 Homo sapiens four and a half LIM domains 2 (FHL2), transcript 204 variant 4, mRNA. FHL2 intronic NM 001039492 Homo sapiens four and a half LIM domains 2 (FHL2), transcript 205 variant 5, mRNA. FHL2 intronic NM 001450 Homo sapiens four and a half LIM domains 2 (FHL2), transcript 206 variant 1, mRNA. FHL2 intronic NM 201555 Homo sapiens four and a half LIM domains 2 (FHL2), transcript 207 variant 2, mRNA. MIR4267 exonic NR 036225 Homo sapiens microRNA 4267 (MIR4267), microRNA. 208 MALL exonic NM 005434 Homo sapiens mal, T-cell differentiation protein-like (MALL), 209 mRNA. MIR4436B1 exonic NR 039941 Homo sapiens microRNA 4436b-1 (MIR4436B1), microRNA. 210 MIR4436B2 exonic NR 049830 Homo sapiens microRNA 4436b-2 (MIR4436B2), microRNA. 211 MGAT5 intronic NM 002410 Homo sapiens mannosyl (alpha-1,6-)-glycoprotein beta-1,6-N- 212 acetyl-glucosaminyltransferase (MGAT5), mRNA. BMPR2 intronic NM 001204 Homo sapiens bone morphogenetic protein receptor, type II 213 (serine/threonine kinase) (BMPR2), mRNA. DNER intronic NM 139072 Homo sapiens delta/notch-like EGF repeat containing (DNER), 214 mRNA. IQCB1 exonic NM 001023570 Homo sapiens IQ motif containing B1 (IQCB1), transcript variant 215 1, mRNA. IQCB1 exonic NM 001023571 Homo sapiens IQ motif containing B1 (IQCB1), transcript variant 216 3, mRNA. STIM2 intronic NM 001169117 Homo sapiens stromal interaction molecule 2 (STIM2), transcript 217 variant 3, mRNA. STIM2 intronic NM 001169118 Homo sapiens stromal interaction molecule 2 (STIM2), transcript 218 variant 1, mRNA. STIM2 intronic NM 020860 Homo sapiens stromal interaction molecule 2 (STIM2), transcript 219 variant 2, mRNA. PDGFRA exonic NM 006206 Homo sapiens platelet-derived growth factor receptor, alpha 220 polypeptide (PDGFRA), mRNA. HCN1 exonic NM 021072 Homo sapiens hyperpolarization activated cyclic nucleotide-gated 221 potassium channel 1 (HCN1), mRNA. EMB exonic NM 198449 Homo sapiens embigin (EMB), mRNA. 222 EDIL3 intronic NM 005711 Homo sapiens EGF-like repeats and discoidin I-like domains 3 223 (EDIL3), transcript variant 1, mRNA. MAPK9 exonic NM 002752 Homo sapiens mitogen-activated protein kinase 9 (MAPK9), 224 transcript variant JNK2-a2, mRNA. MAPK9 exonic NM 139068 Homo sapiens mitogen-activated protein kinase 9 (MAPK9), 225 transcript variant JNK2-a1, mRNA. MAPK9 exonic NM 139069 Homo sapiens mitogen-activated protein kinase 9 (MAPK9), 226 transcript variant JNK2-b1, mRNA. MAPK9 exonic NM 139070 Homo sapiens mitogen-activated protein kinase 9 (MAPK9), 227 transcript variant JNK2-b2, mRNA. MAPK9 exonic NM 001135044 Homo sapiens mitogen-activated protein kinase 9 (MAPK9), 228 transcript variant JNK2-g, mRNA. SERPINB6 exonic NM 001271825 Homo sapiens serpin peptidase inhibitor, clade B (ovalbumin), 229 member 6 (SERPINB6), transcript variant 6, mRNA. SERPINB6 exonic NM 001271823 Homo sapiens serpin peptidase inhibitor, clade B (ovalbumin), 230 member 6 (SERPINB6), transcript variant 4, mRNA. SERPINB6 exonic NM 001271822 Homo sapiens serpin peptidase inhibitor, clade B (ovalbumin), 231 member 6 (SERPINB6), transcript variant 3, mRNA. SERPINB6 exonic NM 001195291 Homo sapiens serpin peptidase inhibitor, clade B (ovalbumin), 232 member 6 (SERPINB6), transcript variant 2, mRNA. SERPINB6 exonic NM 001271824 Homo sapiens serpin peptidase inhibitor, clade B (ovalbumin), 233 member 6 (SERPINB6), transcript variant 5, mRNA. SERPINB6 exonic NM 004568 Homo sapiens serpin peptidase inhibitor, clade B (ovalbumin), 234 member 6 (SERPINB6), transcript variant 1, mRNA. DKFZP686I exonic NR 026855 Homo sapiens long intergenic non-protein coding RNA 1011 235 15217 (LINC01011), transcript variant 1, non-coding RNA. DKFZP686I exonic NR 026856 Homo sapiens long intergenic non-protein coding RNA 1011 236 15217 (LINC01011), transcript variant 2, non-coding RNA. NQO2 exonic NM 000904 Homo sapiens NAD(P)H dehydrogenase, quinone 2 (NQO2), 237 mRNA. HTATSF1P2 exonic NR 033884 Homo sapiens HIV-1 Tat specific factor 1 pseudogene 2 238 (HTATSF1P2), non-coding RNA. PKHD1 intronic NM 138694 Homo sapiens polycystic kidney and hepatic disease 1 (autosomal 239 recessive) (PKHD1), transcript variant 1, mRNA. PKHD1 intronic NM 170724 Homo sapiens polycystic kidney and hepatic disease 1 (autosomal 240 recessive) (PKHD1), transcript variant 2, mRNA. SLC17A5 both NM 012434 Homo sapiens solute carrier family 17 (acidic sugar transporter), 241 member 5 (SLC17A5), mRNA. PDSS2 exonic NM 020381 Homo sapiens prenyl (decaprenyl) diphosphate synthase, subunit 2 242 (PDSS2), mRNA. KCTD7 exonic NM 001167961 Homo sapiens potassium channel tetramerization domain 243 containing 7 (KCTD7), transcript variant 2, mRNA. KCTD7 exonic NM 153033 Homo sapiens potassium channel tetramerization domain 244 containing 7 (KCTD7), transcript variant 1, mRNA. PTPRN2 intronic NM 002847 Homo sapiens protein tyrosine phosphatase, receptor type, N 245 polypeptide 2 (PTPRN2), transcript variant 1, mRNA. PTPRN2 intronic NM 130842 Homo sapiens protein tyrosine phosphatase, receptor type, N 246 polypeptide 2 (PTPRN2), transcript variant 2, mRNA. PTPRN2 intronic NM 130843 Homo sapiens protein tyrosine phosphatase, receptor type, N 247 polypeptide 2 (PTPRN2), transcript variant 3, mRNA. MIR595 exonic NR 030325 Homo sapiens microRNA 595 (MIR595), microRNA. 248 TNFRSF10A exonic NM 003844 Homo sapiens tumor necrosis factor receptor superfamily, member 249 10a (TNFRSF10A), mRNA. IDO2 intronic NM 194294 Homo sapiens indoleamine 2,3-dioxygenase 2 (IDO2), mRNA. 250 STK3 intronic NM 001256313 Homo sapiens serine/threonine kinase 3 (STK3), transcript variant 251 3, mRNA. STK3 intronic NM 006281 Homo sapiens serine/threonine kinase 3 (STK3), transcript variant 252 1, mRNA. STK3 intronic NM 001256312 Homo sapiens serine/threonine kinase 3 (STK3), transcript variant 253 2, mRNA. KANK1 intronic NM 001256876 Homo sapiens KN motif and ankyrin repeat domains 1 (KANK1), 254 transcript variant 3, mRNA. KANK1 intronic NM 001256877 Homo sapiens KN motif and ankyrin repeat domains 1 (KANK1), 255 transcript variant 4, mRNA. KANK1 intronic NM 015158 Homo sapiens KN motif and ankyrin repeat domains 1 (KANK1), 256 transcript variant 1, mRNA. KANK1 intronic NM 153186 Homo sapiens KN motif and ankyrin repeat domains 1 (KANK1), 257 transcript variant 2, mRNA. GDA exonic NM 001242507 Homo sapiens guanine deaminase (GDA), transcript variant 4, 258 mRNA. GDA exonic NM 001242505 Homo sapiens guanine deaminase (GDA), transcript variant 1, 259 mRNA. GDA exonic NM 001242506 Homo sapiens guanine deaminase (GDA), transcript variant 3, 260 mRNA. GDA exonic NM 004293 Homo sapiens guanine deaminase (GDA), transcript variant 2, 261 mRNA. AUH exonic NM 001698 Homo sapiens AU RNA binding protein/enoyl-CoA hydratase 262 (AUR), mRNA. MIR3163 exonic NR 036121 Homo sapiens microRNA 3163 (MIR3163), microRNA. 263 NFIL3 exonic NM 005384 Homo sapiens nuclear factor, interleukin 3 regulated (NFIL3), 264 mRNA. MIR3910-1 exonic NR 037472 Homo sapiens microRNA 3910-1 (MIR3910-1), microRNA. 265 MIR3910-2 exonic NR 037489 Homo sapiens microRNA 3910-2 (MIR3910-2), microRNA. 266 ASTN2 intronic NM 014010 Homo sapiens astrotactin 2 (ASTN2), transcript variant 1, mRNA. 267 ASTN2 intronic NM 198186 Homo sapiens astrotactin 2 (ASTN2), transcript variant 2, mRNA. 268 ASTN2 intronic NM 001184734 Homo sapiens astrotactin 2 (ASTN2), transcript variant 5, mRNA. 269 ASTN2 intronic NM 198187 Homo sapiens astrotactin 2 (ASTN2), transcript variant 3, mRNA. 270 ASTN2 intronic NM 198188 Homo sapiens astrotactin 2 (ASTN2), transcript variant 4, mRNA. 271 ASTN2 intronic NM 001184735 Homo sapiens astrotactin 2 (ASTN2), transcript variant 6, mRNA. 272 LARP4B exonic NM 015155 Homo sapiens La ribonucleoprotein domain family, member 4B 273 (LARP4B), mRNA. GTPBP4 exonic NM 012341 Homo sapiens GTP binding protein 4 (GTPBP4), mRNA. 274 IDI2 exonic NM 033261 Homo sapiens isopentenyl-diphosphate delta isomerase 2 (IDI2), 275 mRNA. IDI2-AS1 exonic NR 024628 Homo sapiens IDI2 antisense RNA 1 (1D12-AS1), transcript 276 variant 1, non-coding RNA. IDI2-AS1 exonic NR 024629 Homo sapiens IDI2 antisense RNA 1 (1D12-AS1), transcript 277 variant 2, non-coding RNA. IDI2-AS1 exonic NR 027708 Homo sapiens IDI2 antisense RNA 1 (1D12-AS1), transcript 278 variant 3, non-coding RNA. IDI2-AS1 exonic NR 027709 Homo sapiens IDI2 antisense RNA 1 (1D12-AS1), transcript 279 variant 4, non-coding RNA. KAT6B exonic NM 001256468 Homo sapiens K(lysine) acetyltransferase 6B (KAT6B), transcript 280 variant 2, mRNA. KAT6B exonic NM 001256469 Homo sapiens K(lysine) acetyltransferase 6B (KAT6B), transcript 281 variant 3, mRNA. KAT6B exonic NM 012330 Homo sapiens K(lysine) acetyltransferase 6B (KAT6B), transcript 282 variant 1, mRNA. VWA2 exonic NM 001272046 Homo sapiens von Willebrand factor A domain containing 2 283 (VWA2), mRNA. PDE3B intronic NM 000922 Homo sapiens phosphodiesterase 3B, cGMP-inhibited (PDE3B), 284 mRNA. EHF intronic NM 001206615 Homo sapiens ets homologous factor (EHF), transcript variant 3, 285 mRNA. EHF intronic NM 012153 Homo sapiens ets homologous factor (EHF), transcript variant 2, 286 mRNA. EHF exonic NM 001206616 Homo sapiens ets homologous factor (EHF), transcript variant 1, 287 RNA. SLC3A2 exonic NM 001012662 Homo sapiens solute carrier family 3 (amino acid transporter heavy 288 chain), member 2 (SLC3A2), transcript variant 2, mRNA. SLC3A2 intronic NM 001012664 Homo sapiens solute carrier family 3 (amino acid transporter heavy 289 chain), member 2 (SLC3A2), transcript variant 5, mRNA. SLC3A2 exonic NM 002394 Homo sapiens solute carrier family 3 (amino acid transporter heavy 290 chain), member 2 (SLC3A2), transcript variant 3, mRNA. SLC3A2 intronic NM 001013251 Homo sapiens solute carrier family 3 (amino acid transporter heavy 291 chain), member 2 (SLC3A2), transcript variant 6, mRNA. SLC3A2 intronic NR 037193 Homo sapiens solute carrier family 3 (amino acid transporter heavy 292 chain), member 2 (SLC3A2), transcript variant 7, non-coding RNA. GDPD4 exonic NM 182833 Homo sapiens glycerophosphodiester phosphodiesterase domain 293 containing 4 (GDPD4), mRNA. ETV6 exonic NM 001987 Homo sapiens ets variant 6 (ETV6), mRNA. 294 LOH12CR1 exonic NM 058169 Homo sapiens loss of heterozygosity, 12, chromosomal region 1 295 (LOH12CR1), mRNA. DUSP16 exonic NM 030640 Homo sapiens dual specificity phosphatase 16 (DUSP16), mRNA. 296 CREBL2 exonic NM 001310 Homo sapiens cAMP responsive element binding protein-like 2 297 (CREBL2), mRNA. GPR19 exonic NM 006143 Homo sapiens G protein-coupled receptor 19 (GPR19), mRNA. 298 CDKN1B exonic NM 004064 Homo sapiens cyclin-dependent kinase inhibitor 1B (p27, Kipl) 299 (CDKN1B),mRNA. APOLD1 exonic NM 001130415 Homo sapiens apolipoprotein L domain containing 1 (APOLD1), 300 transcript variant 1, mRNA. APOLD1 intronic NM 030817 Homo sapiens apolipoprotein L domain containing 1 (APOLD1), 301 transcript variant 2, mRNA. EEA1 exonic NM 003566 Homo sapiens early endosome antigen 1 (EEA1), mRNA. 302 L0C643339 exonic NR 040096 Homo sapiens uncharacterized L00643339 (L00643339), non- 303 coding RNA. NUDT4 exonic NM 019094 Homo sapiens nudix (nucleoside diphosphate linked moiety X)-type 304 motif 4 (NUDT4), transcript variant 1, mRNA. NUDT4 exonic NM 199040 Homo sapiens nudix (nucleoside diphosphate linked moiety X)-type 305 motif 4 (NUDT4), transcript variant 2, mRNA. NUDT4P1 exonic NR 002212 Homo sapiens nudix (nucleoside diphosphate linked moiety X)-type 306 motif 4 pseudogene 1 (NUDT4P1), non-coding RNA. UBE2N exonic NM 003348 Homo sapiens ubiquitin-conjugating enzyme E2N (UBE2N), 307 mRNA. MRPL42 exonic NM 014050 Homo sapiens mitochondrial ribosomal protein L42 (MRPL42), 308 transcript variant 1, mRNA. MRPL42 exonic NM 172177 Homo sapiens mitochondrial ribosomal protein L42 (MRPL42), 309 transcript variant 2, mRNA. MRPL42 exonic NR 038159 Homo sapiens mitochondrial ribosomal protein L42 (MRPL42), 310 transcript variant 3, non-coding RNA. MRPL42 exonic NR 038160 Homo sapiens mitochondrial ribosomal protein L42 (MRPL42), 311 transcript variant 4, non-coding RNA. MRPL42 exonic NR 038161 Homo sapiens mitochondrial ribosomal protein L42 (MRPL42), 312 transcript variant 5, non-coding RNA. SOCS2-AS1 exonic NR 038263 Homo sapiens SOCS2 antisense RNA 1 (SOCS2-AS1), 313 non-coding RNA. SOCS2 exonic NM 003877 Homo sapiens suppressor of cytokine signaling 2 (SOCS2), 314 transcript variant 1, mRNA. SOCS2 exonic NM 001270467 Homo sapiens suppressor of cytokine signaling 2 (SOCS2), 315 transcript variant 2, mRNA. SOCS2 exonic NM 001270468 Homo sapiens suppressor of cytokine signaling 2 (SOCS2), 316 transcript variant 3, mRNA. SOCS2 exonic NM 001270469 Homo sapiens suppressor of cytokine signaling 2 (SOCS2), 317 transcript variant 4, mRNA. SOCS2 exonic NM 001270470 Homo sapiens suppressor of cytokine signaling 2 (SOCS2), 318 transcript variant 5, mRNA. SOCS2 exonic NM 001270471 Homo sapiens suppressor of cytokine signaling 2 (SOCS2), 319 transcript variant 6, mRNA. CRADD exonic NM 003805 Homo sapiens CASP2 and RIPK1 domain containing adaptor with 320 death domain (CRADD), mRNA. PLXNC1 exonic NM 005761 Homo sapiens plexin C1 (PLXNC1), transcript variant 1, mRNA. 321 PLXNC1 exonic NR 037687 Homo sapiens plexin C1 (PLXNC1), transcript variant 2, 322 non-coding RNA. CCDC41 exonic NM 001042399 Homo sapiens coiled-coil domain containing 41 (CCDC41), 323 transcript variant 2, mRNA. CCDC41 exonic NM 016122 Homo sapiens coiled-coil domain containing 41 (CCDC41), 324 transcript variant 1, mRNA. TRAFD1 exonic NM 001143906 Homo sapiens TRAF-type zinc finger domain containing 1 325 (TRAFD1), transcript variant 1, mRNA. TRAFD1 exonic NM 006700 Homo sapiens TRAF-type zinc finger domain containing 1 326 (TRAFD1), transcript variant 2, mRNA. RGCC exonic NM 014059 Homo sapiens regulator of cell cycle (RGCC), mRNA. 327 COMMD6 exonic NM 203495 Homo sapiens COMM domain containing 6 (COMMD6), transcript 328 variant 2, mRNA. COMMD6 exonic NM 203497 Homo sapiens COMM domain containing 6 (COMMD6), transcript 329 variant 1, mRNA. GPC5 intronic NM 004466 Homo sapiens glypican 5 (GPC5), mRNA. 330 ARHGEF7 exonic NM 003899 Homo sapiens Rho guanine nucleotide exchange factor (GEF) 7 331 (ARHGEF7), transcript variant 1, mRNA. ARHGEF7 exonic NM 001113513 Homo sapiens Rho guanine nucleotide exchange factor (GEF) 7 332 (ARHGEF7), transcript variant 5, mRNA. TEX29 exonic NM 152324 Homo sapiens testis expressed 29 (TEX29), mRNA. 333 ARHGEF7 intronic NM 001113511 Homo sapiens Rho guanine nucleotide exchange factor (GEF) 7 334 (ARHGEF7), transcript variant 3, mRNA. ARHGEF7 intronic NM 001113512 Homo sapiens Rho guanine nucleotide exchange factor (GEF) 7 335 (ARHGEF7), transcript variant 4, mRNA. ARHGEF7 intronic NM 145735 Homo sapiens Rho guanine nucleotide exchange factor (GEF) 7 336 (ARHGEF7), transcript variant 2, mRNA. RNASE10 exonic NM 001012975 Homo sapiens ribonuclease, RNase A family, 10 (non-active) 337 (RNASE10),mRNA. RNASE3 exonic NM 002935 Homo sapiens ribonuclease, RNase A family, 3 (RNASE3), 338 mRNA. ECRP exonic NR 033909 Homo sapiens ribonuclease, RNase A family, 2 (liver, eosinophil- 339 derived neurotoxin) pseudogene (ECRP), non-coding RNA. PRKCH intronic NM 006255 Homo sapiens protein kinase C, eta (PRKCH), mRNA. 340 MTHFD1 exonic NM 005956 Homo sapiens methylenetetrahydrofolate dehydrogenase (NADP + 341 dependent) 1, methenyltetrahydrofolate cyclohydrolase, formyhetrahydrofolate synthetase (MTHFD1), mRNA. BDKRB2 intronic NM 000623 Homo sapiens bradykinin receptor B2 (BDKRB2), mRNA. 342 HEXA exonic NM 000520 Homo sapiens hexosaminidase A (alpha polypeptide) (HEXA), 343 mRNA. PSTPIP1 exonic NM 003978 Homo sapiens proline-serine-threonine phosphatase interacting 344 protein 1 (PSTPIP1), mRNA. RBFOX1 intronic NM 001142333 Homo sapiens RNA binding protein, fox-1 homolog (C. elegans) 1 (RBFOX1), transcript variant 5, mRNA. 345 RBFOX1 intronic NM 018723 Homo sapiens RNA binding protein, fox-1 homolog (C. elegans) 1 (RBFOX1), transcript variant 4, mRNA. 346 RBFOX1 intronic NM 001142334 Homo sapiens RNA binding protein, fox-1 homolog (C. elegans) 1 (RBFOX1), transcript variant 6, mRNA. 347 RBFOX1 intronic NM 145891 Homo sapiens RNA binding protein, fox-1 homolog (C. elegans) 1 348 (RBFOX1), transcript variant 1, mRNA. RBFOX1 intronic NM 145892 Homo sapiens RNA binding protein, fox-1 homolog (C. elegans) 1 349 (RBFOX1), transcript variant 2, mRNA. RBFOX1 intronic NM 145893 Homo sapiens RNA binding protein, fox-1 homolog (C. elegans) 1 350 (RBFOX1), transcript variant 3, mRNA. PRKCB both NM 002738 Homo sapiens protein kinase C, beta (PRKCB), transcript variant 2, 351 mRNA. PRKCB both NM 212535 Homo sapiens protein kinase C, beta (PRKCB), transcript variant 1, 352 mRNA. FUK both NM 145059 Homo sapiens fucokinase (FUK), mRNA. 353 COG4 exonic NM 001195139 Homo sapiens component of oligomeric golgi complex 4 (COG4), 354 transcript variant 2, mRNA. COG4 exonic NM 015386 Homo sapiens component of oligomeric golgi complex 4 (COG4), 355 transcript variant 1, mRNA. HPR exonic NM 020995 Homo sapiens haptoglobin-related protein (HPR), mRNA. 356 RPL38 exonic NM 000999 Homo sapiens ribosomal protein L38 (RPL38), transcript variant 1, 357 mRNA. RPL38 exonic NM 001035258 Homo sapiens ribosomal protein L38 (RPL38), transcript variant 2, 358 mRNA. MGC16275 exonic NR 026914 Homo sapiens uncharacterized protein MGC16275 (MGC16275), 359 non-coding RNA. TTYH2 exonic NM 032646 Homo sapiens tweety family member 2 (TTYH2), transcript variant 360 1, mRNA. TTYH2 exonic NM 052869 Homo sapiens tweety family member 2 (TTYH2), transcript variant 361 2, mRNA. DNAI2 exonic NM 001172810 Homo sapiens dynein, axonemal, intermediate chain 2 (DNAI2), 362 transcript variant 2, mRNA. DNAI2 exonic NM 023036 Homo sapiens dynein, axonemal, intermediate chain 2 (DNAI2), 363 transcript variant 1, mRNA. KIF19 exonic NM 153209 Homo sapiens kinesin family member 19 (KIF19), mRNA. 364 BTBD17 exonic NM 001080466 Homo sapiens BTB (POZ) domain containing 17 (BTBD17), 365 mRNA. GPR142 exonic NM 181790 Homo sapiens G protein-coupled receptor 142 (GPR142), mRNA. 366 GPRC5C exonic NM 022036 Homo sapiens G protein-coupled receptor, family C, group 5, 367 member C (GPRC5C), transcript variant 1, mRNA. GPRC5C exonic NM 018653 Homo sapiens G protein-coupled receptor, family C, group 5, 368 member C (GPRC5C), transcript variant 2, mRNA. CD300A exonic NM 001256841 Homo sapiens CD300a molecule (CD300A), transcript variant 2, 369 mRNA. CD300A exonic NM 007261 Homo sapiens CD300a molecule (CD300A), transcript variant 1, 370 mRNA. CD300LB exonic NM 174892 Homo sapiens CD300 molecule-like family member b (CD300LB), 371 mRNA. CD300C exonic NM 006678 Homo sapiens CD300c molecule (CD300C), mRNA. 372 CD300LD exonic NM 001115152 Homo sapiens CD300 molecule-like family member d (CD300LD), 373 mRNA. C17orf77 exonic NM 152460 Homo sapiens chromosome 17 open reading frame 77 (C17orf77), 374 mRNA. CD300E exonic NM 181449 Homo sapiens CD300e molecule (CD300E), mRNA. 375 RAB37 exonic NM 175738 Homo sapiens RAB37, member RAS oncogene family (RAB37), 376 transcript variant 3, mRNA. CD300LF exonic NM139018 Homo sapiens CD300 molecule-like family member f (CD300LF), 377 mRNA. RAB37 intronic NM 001163989 Homo sapiens RAB37, member RAS oncogene family (RAB37), 378 transcript variant 4, mRNA. RAB37 intronic NM 001006638 Homo sapiens RAB37, member RAS oncogene family (RAB37), 379 transcript variant 2, mRNA. RAB37 intronic NM 001163990 Homo sapiens RAB37, member RAS oncogene family (RAB37), 380 transcript variant 5, mRNA. TBC1D16 intronic NM 019020 Homo sapiens TBC1 domain family, member 16 (TBC1D16), 381 transcript variant 1, mRNA. TBC1D16 intronic NM 001271844 Homo sapiens TBC1 domain family, member 16 (TBC1D16), 382 transcript variant 2, mRNA. TBC1D16 intronic NM 001271845 Homo sapiens TBC1 domain family, member 16 (TBC1D16), 383 transcript variant 3, mRNA. TBC1D16 intronic NM 001271846 Homo sapiens TBC1 domain family, member 16 (TBC1D16), 384 transcript variant 4, mRNA. RPTOR intronic NM 001163034 Homo sapiens regulatory associated protein of MTOR, complex 1 385 (RPTOR), transcript variant 2, mRNA. RPTOR intronic NM 020761 Homo sapiens regulatory associated protein of MTOR, complex 1 386 (RPTOR), transcript variant 1, mRNA. PTPN2 exonic NM 001207013 Homo sapiens protein tyrosine phosphatase, non-receptor type 2 387 (PTPN2), transcript variant 4, mRNA. PTPN2 exonic NM 080422 Homo sapiens protein tyrosine phosphatase, non-receptor type 2 388 (PTPN2), transcript variant 2, mRNA. PTPN2 exonic NM 080423 Homo sapiens protein tyrosine phosphatase, non-receptor type 2 389 (PTPN2), transcript variant 3, mRNA. PTPN2 intronic NM 002828 Homo sapiens protein tyrosine phosphatase, non-receptor type 2 390 (PTPN2), transcript variant 1, mRNA. ST8SIA5 exonic NM 013305 Homo sapiens ST8 alpha-N-acetyl-neuraminide alpha-2,8- 391 sialyltransferase 5 (ST8SIA5), mRNA. PIAS2 exonic NM 004671 Homo sapiens protein inhibitor of activated STAT, 2 (PIAS2), 392 transcript variant beta, mRNA. PIAS2 exonic NM 173206 Homo sapiens protein inhibitor of activated STAT, 2 (PIAS2), 393 transcript variant alpha, mRNA. SERPINTB4 exonic NM 002974 Homo sapiens serpin peptidase inhibitor, clade B (ovalbumin), 394 member 4 (SERPINTB4),mRNA. FLJ26850 intronic NR 027257 Homo sapiens FLJ26850 protein (FLJ26850), non-coding RNA. 395 FPR2 exonic NM 001005738 Homo sapiens formyl peptide receptor 2 (FPR2), transcript variant 396 2, mRNA. FPR2 exonic NM 001462 Homo sapiens formyl peptide receptor 2 (FPR2), transcript variant 397 1, mRNA. FPR3 exonic NM 002030 Homo sapiens formyl peptide receptor 3 (FPR3), mRNA. 398 ZNF577 exonic NR 0241813 Homo sapiens zinc finger protein 577 (ZNF577), transcript variant, 399 non-coding RNA. ZNF577 exonic NM 001135590 Homo sapiens zinc finger protein 577 (ZNF577), transcript variant 400 2, mRNA. ZNF577 exonic NM 032679 Homo sapiens zinc finger protein 577 (ZNF577), transcript variant 401 1, mRNA. ZNF649 exonic NM 023074 Homo sapiens zinc finger protein 649 (ZNF649), mRNA. 402 ZNF613 exonic NM 001031721 Homo sapiens zinc finger protein 613 (ZNF613), transcript variant 403 1, mRNA. ZNF613 exonic NM 024840 Homo sapiens zinc finger protein 613 (ZNF613), transcript variant 404 2, mRNA. ZNF350 exonic NM 021632 Homo sapiens zinc finger protein 350 (ZNF350), mRNA. 405 ZNF615 exonic NM 001199324 Homo sapiens zinc finger protein 615 (ZNF615), transcript variant 406 1, mRNA. ZNF615 exonic NM198480 Homo sapiens zinc finger protein 615 (ZNF615), transcript variant 407 2, mRNA. ZNF614 exonic NM 025040 Homo sapiens zinc finger protein 614 (ZNF614), mRNA. 408 ZNF432 exonic NM 014650 Homo sapiens zinc finger protein 432 (ZNF432), mRNA. 409 ZNF841 exonic NM 001136499 Homo sapiens zinc finger protein 841 (ZNF841), mRNA. 410 NLRP12 exonic NM 001277126 Homo sapiens NLR family, pyrin domain containing 12 (NLRP12), 411 transcript variant 3, mRNA. NLRP12 exonic NM 001277129 Homo sapiens NLR family, pyrin domain containing 12 (NLRP12), 412 transcript variant 4, mRNA. NLRP12 exonic NM 144687 Homo sapiens NLR family, pyrin domain containing 12 (NLRP12), 413 transcript variant 2, mRNA. VSTM1 intronic NM 198481 Homo sapiens V-set and transmembrane domain containing 1 414 (VSTM1), mRNA. SNX5 exonic NM 014426 Homo sapiens sorting nexin 5 (SNX5), transcript variant 2, mRNA. 415 SNX5 exonic NM 152227 Homo sapiens sorting nexin 5 (SNX5), transcript variant 1, mRNA. 416 SNORD17 exonic NR 003045 Homo sapiens small nucleolar RNA, C/D box 17 (SNORD17), 417 small nucleolar RNA. MGME1 exonic NM 052865 Homo sapiens mitochondrial genome maintenance exonuclease 1 418 (MGME1), mRNA. OVOL2 exonic NM 021220 Homo sapiens ovo-like 2 (Drosophila) (OVOL2), mRNA. 419 ADA intronic NM 000022 Homo sapiens adenosine deaminase (ADA), mRNA. 420 NRIP1 exonic NM 003489 Homo sapiens nuclear receptor interacting protein 1 (NRIP1), 421 mRNA. BACH1 exonic NR 027655 Homo sapiens BTB and CNC homology 1, basic leucine zipper 422 transcription factor 1 (BACH1), transcript variant 3, non-coding RNA. BACH1 intronic NM 001186 Homo sapiens BTB and CNC homology 1, basic leucine zipper 423 transcription factor 1 (BACH1), transcript variant 2, mRNA. BACH1 intronic NM 206866 Homo sapiens BTB and CNC homology 1, basic leucine zipper 424 transcription factor 1 (BACH1), transcript variant 1, mRNA. TRPM2 exonic NM 003307 Homo sapiens transient receptor potential cation channel, subfamily 425 M, member 2 (TRPM2), transcript variant 1, mRNA. TRPM2 exonic NR 038257 Homo sapiens transient receptor potential cation channel, subfamily 426 M, member 2 (TRPM2), transcript variant 2, non-coding RNA. ADARB1 intronic NM 001112 Homo sapiens adenosine deaminase, RNA-specific, B1 (ADARB1), transcript variant 1, mRNA. 427 ADARB1 intronic NM 001160230 Homo sapiens adenosine deaminase, RNA-specific, B1 (ADARB1), 428 transcript variant 7, mRNA. ADARB1 intronic NM 015833 Homo sapiens adenosine deaminase, RNA-specific, B1 (ADARB1), 429 transcript variant 2, mRNA. ADARB1 intronic NM 015834 Homo sapiens adenosine deaminase, RNA-specific, B1 (ADARB1), 430 transcript variant 3, mRNA. ADARB1 intronic NR027672 Homo sapiens adenosine deaminase, RNA-specific, B1 (ADARB1), 431 transcript variant 5, non-coding RNA. ADARB1 intronic NR 027673 Homo sapiens adenosine deaminase, RNA-specific, B1 (ADARB1), 432 transcript variant 4, non-coding RNA. ADARB1 intronic NR 027674 Homo sapiens adenosine deaminase, RNA-specific, B1 (ADARB1), 433 transcript variant 6, non-coding RNA. ADARB1 intronic NR 073200 Homo sapiens adenosine deaminase, RNA-specific, B1 (ADARB1), 434 transcript variant 8, non-coding RNA. APOBEC3A exonic NM 001270406 Homo sapiens apolipoprotein B mRNA editing enzyme, catalytic 435 polypeptide-like 3A (APOBEC3A), transcript variant 3, mRNA. APOBEC3A exonic NM 145699 Homo sapiens apolipoprotein B mRNA editing enzyme, catalytic 436 polypeptide-like 3A (APOBEC3A), transcript variant 1, mRNA. APOBEC3AB intronic NM 001193289 Homo sapiens APOBEC3A and APOBEC3B deletion hybrid 437 (APOBEC3AB), mRNA. APOBEC3B exonic NM 001270411 Homo sapiens apolipoprotein B mRNA editing enzyme, catalytic 438 polypeptide-like 3B (APOBEC3B), transcript variant 2, mRNA. APOBEC3B exonic NM 004900 Homo sapiens apolipoprotein B mRNA editing enzyme, catalytic 439 polypeptide-like 3B (APOBEC3B), transcript variant 1, mRNA. MKL1 intronic NM 020831 Homo sapiens megakaryoblastic leukemia (translocation) 1 440 (MKL1), mRNA. TNFRSF13C exonic NM 052945 Homo sapiens tumor necrosis factor receptor superfamily, member 441 13C (TNFRSF13C), mRNA. CENPM exonic NM 001110215 Homo sapiens centromere protein M (CENPM), transcript variant 442 3, mRNA. CENPM exonic NM 001002876 Homo sapiens centromere protein M (CENPM), transcript variant 443 2, mRNA. CENPM exonic NM 024053 Homo sapiens centromere protein M (CENPM), transcript variant 444 1, mRNA. PPP2R3B intronic NM 013239 Homo sapiens protein phosphatase 2, regulatory subunit B″, beta 445 (PPP2R3B), mRNA. VCX exonic NM 013452 Homo sapiens variable charge, X-linked (VCX), mRNA. 446 PNPLA4 exonic NM 004650 Homo sapiens patatin-like phospholipase domain containing 4 447 (PNPLA4), transcript variant 1, mRNA. PNPLA4 exonic NM 001142389 Homo sapiens patatin-like phospholipase domain containing 4 448 (PNPLA4), transcript variant 2, mRNA. PNPLA4 exonic NM 001172672 Homo sapiens patatin-like phospholipase domain containing 4 449 (PNPLA4), transcript variant 3, mRNA. MIR651 exonic NR 030380 Homo sapiens microRNA 651 (MIR651), microRNA. 450 JPX intronic NR 024582 Homo sapiens JPX transcript, XIST activator (non-protein coding) 451 (JPX), non-coding RNA. GRIA3 intronic NM 000828 Homo sapiens glutamate receptor, ionotropic, AMPA 3 (GRIA3), 452 transcript variant 2, mRNA. GRIA3 intronic NM 007325 Homo sapiens glutamate receptor, ionotropic, AMPA 3 (GRIA3), 453 transcript variant 1, mRNA. GRIA3 intronic NM 001256743 Homo sapiens glutamate receptor, ionotropic, AMPA 3 (GRIA3), 454 transcript variant 3, mRNA. HMGB3 exonic NM 005342 Homo sapiens high mobility group box 3 (HMGB3), mRNA. 455

For all genes listed in Table 2 (namely, those relevant to CNV-subregions of interest), Table 4 represents a non-redundant list.

TABLE 5 The set of SNVs reported in Tables 7-10, 14, or 15 that were found in the 70 PML cases in this study for which WES data were generated. Chromosome Position hg19 REF ALT SEQ ID 1 9777599 C G 1000 1 12172008 T C 1001 1 24486004 G T 1002 1 33476435 C A 1003 1 33478900 T A 1004 1 33487007 C T 1005 1 36932047 C T 1006 1 36933715 A G 1007 1 42047208 C G 1008 1 59248085 G C 1009 1 59248339 T C 1010 1 92941660 C T 1011 1 92946625 G C 1012 1 92946625 G C 1013 1 150053494 C T 1014 1 155317682 C T 1015 1 155449630 T G 1016 1 155450331 C T 1017 1 182554557 C T 1018 1 198717250 T G 1019 1 198717272 A T 1020 1 206945738 C T 1021 1 207641950 C T 1022 1 235840495 G T 1023 1 235897907 C T 1024 1 235909815 A T 1025 2 24431184 C T 1026 2 24432937 C T 1027 2 24435599 G A 1028 2 47205921 C T 1029 2 47273468 A G 1030 2 47277182 T C 1031 2 55910961 T C 1032 2 71337203 C T 1033 2 98351032 C G 1034 2 98351066 C T 1035 2 98351081 C T 1036 2 113589000 C T 1037 2 163124051 C T 1038 2 163133194 T C 1039 2 163134203 G T 1040 2 163136505 C G 1041 2 163139025 C T 1042 2 163139085 A T 1043 2 163144899 G A 1044 2 163174327 C A 1045 2 163174328 T G 1046 2 219942026 T A 1047 2 220023045 C T 1048 2 230231632 C T 1049 2 230450646 T A 1050 3 38181899 G T 1051 3 39323163 A C 1052 3 53213691 G C 1053 3 53221390 T C 1054 3 121415370 T C 1055 3 128204761 C T 1056 3 128205808 C T 1057 3 142272098 A G 1058 3 142274880 G C 1059 3 142281353 C G 1060 3 142286928 C T 1061 3 196199032 A T 1062 3 196199204 G T 1063 3 196210704 G A 1064 3 196210764 T C 1065 3 196214320 C T 1066 4 27019452 C T 1067 4 27024170 A G 1068 4 103522068 A G 1069 4 103522150 G A 1070 4 103528328 C T 1071 4 151199080 G A 1072 4 151520216 G A 1073 4 187003729 C G 1074 4 187004074 C T 1075 4 187005854 A C 1076 5 67591018 A C 1077 5 77311370 C T 1078 5 77311370 C T 1079 5 77334964 T C 1080 5 77334964 T C 1081 5 77335015 G T 1082 5 77335015 G T 1083 5 77437092 G C 1084 5 77437092 G C 1085 5 78596018 G C 1086 5 138856923 C T 1087 5 156593120 C T 1088 5 169081453 G C 1089 6 3077139 T C 1090 6 12121113 C T 1091 6 12122102 T G 1092 6 12123538 G T 1093 6 12124215 C T 1094 6 12125232 C T 1095 6 12162068 C T 1096 6 12163657 C T 1097 6 31928306 A G 1098 6 31935750 G A 1099 6 31936679 C T 1100 6 32797809 C T 1101 6 32810794 T A 1102 6 32811752 C T 1103 6 51483961 T C 1104 6 51484077 G C 1105 6 51491885 G A 1106 6 51497503 C A 1107 6 51524339 C G 1108 6 51524409 G T 1109 6 51612746 G A 1110 6 51712759 T C 1111 6 51747943 T A 1112 6 51798908 C T 1113 6 52101833 C T 1114 6 83884161 C G 1115 6 143081232 T C 1116 6 143092151 T C 1117 6 143092673 G A 1118 6 144508353 G A 1119 6 144508563 G A 1120 7 2959240 C T 1121 7 2962933 C T 1122 7 2983958 T C 1123 8 39840234 A G 1124 8 39862881 C T 1125 8 39862893 T A 1126 8 42176189 G A 1127 8 48690299 A G 1128 8 48773526 T C 1129 8 48798507 T C 1130 8 48826575 C G 1131 8 61654298 T A 1132 8 61732632 A G 1133 8 61757805 C T 1134 8 61769428 A G 1135 8 61777914 C G 1136 8 61777922 C G 1137 8 90990521 T C 1138 8 100205255 G A 1139 8 100791158 G A 1140 8 100865941 G A 1141 8 145154222 G A 1142 8 145154222 G A 1143 8 145154257 C G 1144 8 145154824 A C 1145 9 286491 G A 1146 9 286593 C A 1147 9 304628 G A 1148 9 312134 G A 1149 9 328047 T A 1150 9 334277 G A 1151 9 368128 C T 1152 9 399233 A G 1153 9 446401 A G 1154 9 711359 C T 1155 9 713132 G T 1156 9 32526077 C T 1157 9 32526077 C T 1158 9 120466814 A G 1159 9 120475302 A G 1160 9 120475602 C T 1161 9 120476568 A G 1162 9 120476816 C T 1163 10 1060218 G A 1164 10 14974905 T C 1165 10 14976727 G C 1166 10 14977469 C A, T 1167 10 72358167 G A 1168 10 76602923 G T 1169 10 76748831 C T 1170 10 89720659 G T 1171 10 90771767 G A 1172 10 116045796 G A 1173 11 4104626 C A 1174 11 4112582 C T 1175 11 9598696 G A 1176 11 9608330 G A 1177 11 36595321 C T 1178 11 36596528 G C 1179 11 36596863 C T 1180 11 36597513 G A 1181 11 36614561 G T 1182 11 36615033 C T 1183 11 67814983 G A 1184 11 67818269 G A 1185 11 76954833 G A 1186 11 76979511 A G 1187 11 108117787 C T 1188 11 108119823 T C 1189 11 108123551 C T 1190 11 108138003 T C 1191 11 108143456 C G 1192 11 108175462 G A 1193 11 108181014 A G 1194 11 108186610 G A 1195 11 108186631 A G 1196 11 108198384 C G 1197 11 108202772 G T 1198 12 12673965 G A 1199 12 12870798 G A 1200 12 44166753 A G 1201 12 44167821 A 1 1202 12 64878241 G A 1203 12 64879775 C T 1204 12 88900891 C A 1205 12 93196332 C T 1206 12 93205148 T G 1207 12 112583447 A C 1208 12 122064788 G GT 1209 12 133201381 T A 1210 12 133202816 C T 1211 12 133209020 G C 1212 12 133220526 T C 1213 12 133220544 C T 1214 12 133237658 T G 1215 12 133245026 G A 1216 12 133252406 C A 1217 12 133253971 C T 1218 12 133253995 G A 1219 13 47466549 T C 1220 13 108861092 G T 1221 13 108863591 G A 1222 14 21992397 T C 1223 14 21993359 G A 1224 14 22004996 G T 1225 14 24805463 G T 1226 14 24806303 G A 1227 14 61924007 C G 1228 14 103369593 G A 1229 15 41011016 G A 1230 15 68378781 A C 1231 15 77329479 C T 1232 15 91306241 G A 1233 15 91310209 A G 1234 15 91326099 C T 1235 15 91328219 G T 1236 15 91328310 A G 1237 15 91341543 A C 1238 16 1498408 G A 1239 16 1510535 C T 1240 16 1524855 C G 1241 16 7568296 C T 1242 16 7703891 A G 1243 16 7714909 C T 1244 16 7759119 G A 1245 16 7759496 C T 1246 16 24124365 A G 1247 16 27460020 G A 1248 16 30133233 T C 1249 16 30134529 A C 1250 16 50733536 T C 1251 16 50741791 C T 1252 16 50741791 C T 1253 16 50744688 A G 1254 16 50745021 C T 1255 16 50753867 G T 1256 16 70503095 A G 1257 16 81819605 C T 1258 16 81902826 C T 1259 16 81904539 C T 1260 16 81939089 T C 1261 16 81942028 C G 1262 16 81942175 A G 1263 16 81946278 A G 1264 16 81960772 C A 1265 17 7577069 C T 1266 17 16852187 A G 1267 17 77926526 C T 1268 18 43445580 C T 1269 18 43445601 T G 1270 18 43456296 C T 1271 18 43458306 G A 1272 18 43460105 C A 1273 18 43464763 C T 1274 18 43479473 T C 1275 18 43488030 T C 1276 18 43496370 G A 1277 18 43496539 G A 1278 18 43497710 A G 1279 18 43523240 C T 1280 18 43529551 C T 1281 18 43531186 C T 1282 18 44392443 T C 1283 18 48584504 C T 1284 18 56401523 C T 1285 18 60036429 G A 1286 18 60052034 A C 1287 19 4817657 C T 1288 19 4817852 G A 1289 19 7705818 C T 1290 19 7712287 G C 1291 19 48631258 G A 1292 19 48639022 T C 1293 20 3843027 C A 1294 20 3846397 C T 1295 20 31383307 G A 1296 20 31384614 G T 1297 20 62305450 C T 1298 20 62309621 T C 1299 20 62326964 C G 1300 21 16338814 T C 1301 21 16339852 T C 1302 21 30698953 T G 1303 21 34809232 C T 1304 21 45786650 C T 1305 21 45795833 G T 1306 21 45795877 G T 1307 21 45811411 G T 1308 21 45811438 C T 1309 21 45815307 T C 1310 21 45815331 G A 1311 21 45815343 A G 1312 21 45815425 C G 1313 21 45820196 C T 1314 21 45826486 G A 1315 21 45826616 C T 1316 21 45838333 C T 1317 21 45844780 C T 1318 21 45845528 G A 1319 21 45845661 A G 1320 21 45845699 G A 1321 21 45855099 C T 1322 22 21235389 A G 1323 22 23915583 T C 1324 22 23915745 G A 1325 22 23917192 G T 1326 22 36661354 C T 1327 X 24759574 G T 1328 X 24759574 G T 1329

Table 5 lists, in order of genomic coordinates, all single nucleotide variants (SNVs) that are relevant to the present study, whether as case-level solutions (Tables 7, 8) or potential solutions (Tables 9, 10), or at the level of variant burden analysis (Tables 14, 15). All genome coordinates are based on hg19.

TABLE 6 Non-redundant list of 419 genes involved in the immune system and/or linked to PML via a CNV RefSeq Gene Disease Gene Gene Number Symbol Model Source Source Annotation (GN) ACADM AR Public db MySql 157 ACKR1 AD Public db MySql 158 ACP5 AR Public db PMID: 26052098, 27260006, 27821552 159 ADAR AD AR Public db PMID: 26052098, 27260006, 27821552 160 ADARB1 unknown PBio PMID: 16227093, 17376196, 19482597, 20220309, 21682836, 2 21809195, 22001568, 22085847, 22113393, 24586166, 24725957, 24760760, 25826567 ADK AR PBio PMID: 17205396, 23592612, 25654762, 25720338, 25979489, 161 26341819, 26642971 AGBL4 unknown PBio PMID: 17244818, 21074048, 23085998, 25416787, 25332286, 3 26502776 AICDA AD AR Public db MySql; PMID: 23765059 162 AK2 AR Public db PMID: 19043417, 19782549, 20008220, 23765059, 24135998, 163 24753205, 26454313 ALG12 AR Public db MySql 164 ALPL AD AR PBio PMID: 18821074, 20049532, 20977932, 21191615, 21289095, 165 23091474, 23454488, 23860646, 26219705, 26219711, 26219717 AP3B1 AR Public db MySql; PMID: 11590544, 19782549, 24302998, 24753205, 166 24916509, 25980904, 27889060 AP3B2 AR Public db PMID: 26377319, 27889060 167 AP3D1 AR Public db PMID: 26744459, 27889060 168 APOBEC3A unknown PBio PMID: 16720547, 17303427, 20062055, 20615867, 22896697, 4 23344558, 23640892, 25262471, 25576866, 26416327, 26489798, 26678087 APOBEC3B unknown PBio PMID: 16720547, 17303427, 20062055, 20615867, 22896697, 6 23344558, 23640892, 25262471, 25576866, 26416327, 26489798, 26678087 APOL1 association Public db PMID: 27042682 169 ARHGEF7 unknown PBio PMID: 11160719, 16983070, 18378701, 19861492, 25284783, 8 25500533 ASH1L unknown PBio PMID: 17923682, 17981149, 22541069, 24012418, 24244179, 170 25866973, 26002201, 27154821, 27229316, 27434206 ASTN2 unknown PBio PMID: 2223091, 8602532, 20573900, 24357807, 24381304, 9 25146927, 25410587, 26514622, 26586575 ATL2 unknown PBio PMID: 18270207, 19665976, 25773277 171 ATM AR Public db MySql; PMID: 19903823, 20301790, 23765059, 24799566, 172 25692705, 27042682, 27484032, 27884168, 27895165 ATR AD AR Public db PMID: 17564965, 17151099, 19903823, 20506465, 21615334, 173 24799566, 25910481 AUH AR PBio PMID: 12434311, 12655555, 17130438, 20855850, 25280001, 10 25597510 BACH1 unknown PBio PMID: 15068237, 18555605, 22024395, 22791292, 23456643, 11 23562577, 24752012, 25344725, 25391381, 24752012, 26045540, 26894991 BACH2 unknown PBio PMID: 17262715, 17991429, 18769450, 22791292, 23728300, 174 24367030, 24608439, 24681888, 24694524, 25123280, 25344725, 25665584, 25686607, 26444573, 26620562, 26731475, 26894991, 26981933 BCL10 AR Public db MySql 176 BDKRB2 unknown PBio PMID: 7787759, 18930543, 22047990, 22095814, 24925394 12 BLM AR PBio PMID: 15137905, 15493327, 17210642, 17321898, 19109166, 177 19709744, 2032252, 23572515, 24606147 BLNK AR Public db PMID: 23765059 178 BLOC1S6 AR Public db MySql 179 BMPR2 AD PBio PMID: 15877825, 19191909, 23733693, 24334027 13 C11orf65 unknown Public db MySql 181 C1QA AR Public db PMID: 27821552 182 C1QB AR Public db PMID: 27821552 183 C1QC AR Public db PMID: 27821552 184 C5AR1 unknown PBio PMID: 1847994, 22964232, 25041699, 25174320, 25455139, 185 25539817, 25769922, 26059553, 26283482, 26537334 CAPZB unknown PBio PMID: 99354614, 19806181, 22493691, 22706086, 22710966, 186 22918941, 23178720, 26758871 CARD11 AD AR Public db MySql; PMID: 23765059, 25645939, 26525107 187 CARD9 AR Public db PMID: 27222657 188 CASP8 AR Public db PMID: 22365665, 26454313, 27873163, 27999438 189 CCL11 AD Public db MySql 190 CCL2 association Public db MySql 191 CCL5 association Public db MySql 192 CCR2 association Public db MySql 193 CCR5 association Public db MySql 194 CD180 unknown PBio PMID: 9763566, 10880523, 21918197, 21959264, 22484241, 195 23103284, 23483427, 24019553, 25749095, 26371254, 26384474, 26482097, 26555723, 26371254 CD19 AR Public db MySql; PMID: 23765059, 26453379 196 CD209 association Public db MySql 197 CD247 AR Public db PMID: 26454313 198 CD27 AR Public db MySql; PMID: 23765059 199 CD27-AS1 unknown Public db MySql 200 CD300LF unknown PBio PMID: 15184070, 15549731, 17202342, 18688020, 19592130, 23 22288587, 23072861, 23293083, 24035150 CD34 unknown Public db PMID: 27042682 201 CD3D AR Public db PMID: 23765059, 26454313 202 CD3E AR Public db PMID: 23765059, 26454313 203 CD3G AR Public db PMID: 23765059, 26454313 204 CD40 AR Public db MySql; PMID: 23765059, 26453379 205 CD55 unknown PBio PMID: 12417446, 1385527, 16406700, 16503113, 17678954, 207 18424707, 19660813, 21143144, 22795896, 24588829, 24639397, 25156074, 25954012, 26423932 CD59 AR Public db MySql 208 CD79A AR Public db PMID: 23765059 209 CD79B AR Public db PMID: 23765059 210 CD81 AR Public db MySql 211 CD8A AR Public db PMID: 26454313 212 CDCA7 AR Public db PMID: 26216346 213 CDKN1B AD PBio PMID: 10799578, 10825149, 10916090, 11123298, 11123306, 24 15557280, 16410832, 17273559, 20854895, 21078910, 22454463, 24317118, 25213837 CEBPB unknown Public db PMID: 27042682 214 CENPM unknown PBio PMID: 15183305, 16391015, 19711193, 25006165 25 CHD7 AD Public db PMID: 18505430, 18976358, 26454313, 27484032 215 CHEK1 unknown Public db PMID: 19903823, 27042682 216 CIITA AR Public db PMID: 23765059, 26454313, 27484032 217 CLCN7 AD PMID: 21107136, 25992615 218 COG4 AR PBio PMID: 18086915, 18256213, 20065092, 20143049, 21421995, 26 23462996, 23865579, 24784932, 26125015 COG6 AR Public db MySql 219 COMMD6 unknown PBio PMID: 14685242, 15799966, 16573520, 20126548, 25355947, 27 27441653 CORO1A AR Public db PMID: 23887241, 26454313 220 CR2 AR Public db MySql 221 CRADD AR PBio PMID: 11573962, 21242994, 22323537, 24958727, 26190521, 28 27135977 CRTC3 unknown PBio PMID: 15466468, 2032252, 21536665, 23033494, 23241891, 222 25114223, 25316186, 25351958, 26937622 CSF3R AR Public db PMID: 24753537, 26324699, 27789332 223 CTLA4 AD Public db PMID: 18219311, 25213377, 25329329 224 CTPS1 AR Public db MySql 225 CTSC AR Public db PMID: 27222657 226 CX3CR1 association Public db MySql 227 CXCL12 association Public db MySql 228 CXCL9 unknown Public db PMID: 27042682 229 CXCR1 association Public db MySql 230 CXCR4 AD Public db PMID: 19782549, 19950235, 23765059, 24753205, 25645939, 231 28009639 CXorf40A unknown PBio PMID: 15541360, 24916366, 26881174 232 CYBB XLR Public db PMID: 27222657 233 CYP2S1 unknown PBio PMID: 15681441, 23933117 234 DCLRE1C AR Public db PMID: 26454313, 26476407, 27484032 235 DDX1 unknown Public db PMID: 27042682 236 DDX58 AD Public db PMID: 23592984, 25692705, 25794939, 26052098, 26748340, 237 26848516, 26987611, 27260006, 27821552 DHX58 association Public db PMID: 25794939, 26748340, 26848516 238 DKC1 XLR Public db MySql; PMID: 23765059 239 DNER unknown PBio PMID: 15965470, 16298139, 16997755, 17765022, 18474614, 31 20058045, 20367751, 22447725, 23041955, 23328254, 24248099, 24935874, 26869529 DOCK2 AR Public db MySql 241 DSC1 unknown PBio PMID: 16048752, 20222919, 22692770, 24460202, 24680560, 243 25078507, 25244249, 26043694, 26758100 DUSP16 unknown PBio PMID: 15284860, 21613215, 24311790, 25716993, 26381291, 32 27162525 ECRP unknown PBio PMID: 9826755, 12855582, 25271100, 26184157 33 EDIL3 unknown PBio PMID: 22601780, 23518061, 24060278, 24504014, 25385367, 34 26038125 EEA1 unknown PBio PMID: 16670179, 22591512, 24491918, 24561067, 26478006, 35 26909655, 27077111 EGR1 unknown PBio PMID: 15308739, 19050264, 19812322, 20414733, 21368226, 244 21622185, 22554935, 25613134, 26052046, 26980486, 11910893, 14647476, 18203138, 24627779, 25368162, 27192563 EHF unknown PBio PMID: 16380452, 17027647, 19801549, 20879862, 21617703, 36 24219556, 25217163 ELANE AD Public db PMID: 20008220, 24145314, 27222657 245 EMB unknown PBio PMID: 8432389, 15917240, 18209069, 19164284, 25773908 37 EPG5 AR Public db MySql; PMID: 21965116, 23222957, 23838600, 26917586, 246 26927810, 27588602 ETF1 unknown PBio PMID: 20418372, 25606970, 26384426, 26833392, 27387891 247 ETV6 AD PBio PMID: 19264918, 20350664, 21714648, 22438058, 25581430, 38 25807284, 26718572, 27365488 F9 XLR Public db MySql 248 FAS AD Public db PMID: 27222657 249 FASLG AD Public db PMID: 27222657 250 FCGR2A AD AR Public db MySql 251 FCGR3A AR Public db MySql 252 FCN3 AR Public db MySql 253 FEZ1 unknown Public db PMID: 27042682 254 FHL2 unknown PBio PMID: 16389449, 20592280, 22417706, 22633286, 23212909 39 FOS unknown Public db PMID: 27042682 255 FOXH1 unknown Public db PMID: 27042682 256 FOXN1 AR Public db MySql 257 FOXP3 XLR Public db PMID: 26454313 258 FPR1 unknown PBio PMID: 8994115, 10229829, 10611407, 17084101, 22934745, 259 23230437, 25605714, 25826286, 26101324, 26701131, 27034344, 27100350, 27131862, 27154726 FPR2 unknown PBio PMID: 8994115, 10229829, 10611407, 17084101, 22934745, 41 23230437, 25605714, 25826286, 26101324, 26701131, 27034344, 27100350, 27131862, 27154726 FPR3 unknown PBio PMID: 8994115, 10229829, 10611407, 17084101, 22934745, 42 23230437, 25605714, 25826286, 26101324, 26701131, 27034344, 27100350, 27131862, 27154726 FUK unknown PBio PMID: 11753075, 12651883, 15774760, 19394435, 19647987, 43 20363321, 22134107, 22203233, 22276660, 22461019, 24239607 G6PC3 AR Public db PMID: 20008220, 24145314, 25879134, 26479985 260 GATA2 AD Public db PMID: 23765059, 23887241 261 GDA unknown PBio PMID: 10595517, 18600524, 20826431, 23838888, 24834013 44 GDPD4 unknown PBio PMID: 24373430, 24977479, 24977485, 24977489, 25528375, 45 25596343 GFI1 AD Public db PMID: 20008220, 24145314 262 GOLGB1 unknown PBio PMID: 17475246, 21217069, 22034594, 23555793, 24046448 263 GPATCH2 unknown PBio PMID: 19432882, 25353171, 25376275 46 GPC5 unknown PBio PMID: 24130709, 24943672, 25354479, 26224662, 26349477 47 GPRC5A unknown PBio PMID: 19593893, 20959490, 22239913, 25621293, 25714996, 264 26165721 GRAP2 unknown Public db PMID: 25452106, 25636200, 26246585 265 GRIA3 XLR PBio PMID: 10441169, 12682273, 17202328, 18590483, 25904555, 51 26648591 GTPBP4 unknown PBio PMID: 17785438, 26015807 52 HAX1 AR Public db PMID: 20008220, 24145314 266 HCN1 AD PBio PMID: 9405696, 9630217, 9634236, 9921901, 11133998, 53 23042740, 23077068, 23319474, 24403084, 24747641, 24756635, 25580535, 26578877 HELLS AR Public db PMID: 26216346 267 HEXA AR PBio PMID: 20301397, 21997228, 23727835, 24445368 54 HIVEP1 association Public db MySql; PMID 20226436, 26117544 268 HIVEP2 AD Public db MySql; PMID: 21475200, 21936769, 23389689, 24366360, 269 26153216, 26483320, 27003583 HIVEP3 unknown Public db MySql 270 HK2 unknown PBio PMID: 2749583, 4265132, 19519254, 2496891, 23874603, 55 25525876, 25602755 HMGB3 unknown PBio PMID: 12714519, 15259015, 15358624, 16945912, 22014684, 56 23994280, 26553261 HNRNPLL unknown PBio PMID: 18669861, 18719244, 19100700, 20505149, 22073166, 271 23934048, 24476532, 25825742 HP unknown PBio PMID: 16046400, 19380867, 19795414, 26445729 272 HPCAL1 unknown PBio PMID: 12445467, 24699524, 25519916, 26659654, 26729710 273 HPR unknown PBio PMID: 16046400, 19380867, 19795414, 26445729 57 HTR2A association Public db PMID: 19204164, 24089568, 25078361, 26056932, 27003757, 274 27042682 ICOS AR Public db MySql; PMID: 19380800, 23765059, 27250108 275 IDI1 unknown PBio PMID: 14629038, 17202134, 19454010, 20955688, 22579571, 276 23585482, 25950736 IDI2 unknown PBio PMID: 14629038, 17202134, 19454010, 20955688, 22579571, 59 23585482, 25950736 IDI2-AS1 unknown PBio See IDI2 60 IDO2 unknown PBio PMID: 18219311, 18364004, 19487973, 19799997, 20197554, 61 20484729, 20693847, 21084489, 21406395, 21990421, 22754762, 24391212, 24402311, 24844751, 25477879, 25478733, 25541686, 25949913, 26308414, 27183624 IFIH1 AD Public db PMID: 21156324, 24686847, 24995871, 25794939, 26052098, 277 26748340, 27260006, 27821552 IFNAR1 association Public db PMID: 27821552 278 IFNAR2 AR Public db PMID: 26424569, 27821552 279 IFNG association Public db MySql 280 IFNGR1 AD AR Public db MySql 281 IFNGR2 AD AR Public db MySql; PMID: 15356149, 23161749 282 IFNLR1 unknown PBio PMID: 12469119, 12483210, 15166220, 22386267, 22891284, 62 25634147, 25904743, 25941255 IGLL1 AR Public db PMID: 25502423 283 IKBKB AD AR Public db MySql; PMID: 17047224, 17072332, 25764117, 25930993, 284 26117626, 26525107 IKBKG XLD XLR Public db MySql; PMID: 17047224, 21455173, 21455181, 23765059, 285 25764117, 25886387, 25930993, 26117626, 26525107 IKZF1 AD Public db PMID: 26454313, 26981933 286 IL10 AR Public db PMID: 23887241 287 IL10RA AR Public db PMID: 23887241 288 IL10RB AR Public db PMID: 23887241 289 IL12B AR Public db MySql 290 IL12RB1 AR Public db MySql 291 IL17F AD Public db PMID: 22284928, 23887241, 24240291, 24690400, 25890879, 292 27144517 IL17RA AR Public db PMID: 23887241 293 IL1B AD Public db PMID: 15327898, 20543597, 24248593, 26525107, 27730320, 294 27873163, 27999438 IL21 AR Public db MySql 295 IL21R AD AR Public db PMID: 23765059, 23887241 296 IL2RA AR Public db MySql 297 IL2RG XLR Public db PMID: 23765059, 26454313, 27484032 298 IL4R association Public db MySql 299 IL7 unknown PBio PMID: 21508983, 22288682, 24507157, 24979548, 25130296, 300 25214510, 25411246, 25734144, 26537673, 26675348, 26908786 IL7R AR Public db PMID: 26454313, 27484032 301 IRAK4 AD AR Public db PMID: 23766853, 25232776, 25344726, 25764117, 25886387, 302 25930993, 26785681, 27845762 IRF3 AD Public db PMID: 23388631, 26513235, 26748340 303 IRF7 AR Public db MySql; PMID: 26748340 304 IRF8 AD AR Public db PMID: 23887241 305 IRGM association PBio PMID: 14707092, 17911638, 22174682, 22722598, 23084913, 306 23335927 ISG15 AR Public db MySql; PMID: 26052098, 27260006, 27821552 307 ITSN2 unknown PBio PMID: 11748279, 15020715, 17696400, 17696407, 22558309, 309 22975684, 23986746, 24097067, 24284073, 25797047, 26479042 JAGN1 AR Public db PMID: 25129144 310 JAK3 AR Public db PMID: 23765059, 26454313 311 JMY unknown PBio PMID: 19287377, 20573979, 20574148, 20888769, 21965285, 312 23291261, 25015719, 26223951, 26305109 JPX association PBio PMID: 21029862, 23791181, 23943155 64 JUN unknown Public db PMID: 16928756, 27042682 313 KANK1 association PBio PMID: 18458160, 20164854, 21685469, 24399197, 25961457, 65 26656975 KAT6B AD PBio PMID: 17460191, 17694082, 22715153, 25920810 66 KCTD7 AR PBio PMID: 17455289, 20301601, 21710140, 22606975, 22638565, 67 22748208, 25060828, 27629772, 27742667 KITLG AD Public db PMID: 27042682 314 LAMTOR2 AR Public db MySql; PMID 19782549, 20008220, 24753205 315 LARP4B unknown PBio PMID: 20573744, 23815932, 25534202, 26001795, 26501340, 69 26644407 LCP2 unknown Public db PMID: 12874226, 18219311, 19056831, 23494777, 26246585 317 LIG1 AR Public db MySql 318 LIG4 AR Public db MySql 319 LOC102724297 unknown Public db MySql 320 LOC400710 unknown PBio ncRNA, limited gene information; see SNAR gene family 321 (adjacent locus) LRBA AR Public db MySql; PMID: 23765059, 27873163, 27192563 322 LYST AR Public db PMID: 19302049, 19782549, 20008220, 24753205, 24916509, 323 26454313, 27881733 MAGEA9 unknown PBio PMID: 15222021, 15900605, 21093980, 21791470, 25315972, 324 25445503, 25755744 MAGEA9B unknown PBio PMID: 15222021, 15900605, 21093980, 21791470, 25315972, 325 25445503, 25755744 MAGT1 XLR Public db PMID: 23887241, 27873163, 25504528 326 MALL unknown PBio PMID: 11294831, 19064697, 24101378, 24746959, 26109641, 72 26622604, 26641089, 26772392, 27583248, 27846891 MALT1 AR Public db MySql; PMID: 26525107 327 MAP3K2 unknown PBio PMID: 11032806, 11278622, 12138187, 14734742, 16430878, 328 21333552, 2437584, 24847879, 25012295, 26056008 MAPK1 unknown Public db PMID: 14671106, 27042682 329 MAPK3 unknown Public db PMID: 14671106, 27042682 330 MAPK9 unknown PBio PMID: 15023353, 23685277, 24673683, 25762148, 26141991 73 MAVS association Public db PMID: 23582325, 26513235, 26987611 331 MCEE AR PBio PMID: 17846917, 20301409, 21365456, 23726524, 24532006, 74 25763508, 26725562 MECP2 XLD XLR Public db PMID: 27042682 332 MEX3C unknown PBio PMID: 18779327, 22357625, 22658931, 22863774, 22927639, 333 23140835, 23446422, 23999169, 24706898, 24741071 MGAT5 unknown PBio PMID: 12417426, 15585841, 18292539, 20089585, 20117844, 75 25768892, 26972830 MKL1 AR PBio PMID: 12944485, 22626970, 26098208, 26098211, 26221020, 89 26241940, 26405212, 26224645, 26554816 MRE11A AR Public db PMID: 23388631, 23765059 334 MS4A1 AR Public db MySql; PMID: 23765059 335 MSN unknown PBio PMID: 9070665, 10444190, 11777944, 12445265, 14758359, 336 16368573, 17110458, 18025306, 18725395, 21486194, 23526587, 23613524, 24250818, 24358210, 24760896, 25746045 MTHFD1 AR Both PMID: 26454313 337 MYD88 AD AR Public db PMID: 23766853, 25344726, 25764117, 25886387, 25930993, 338 26371186, 27435819 NBN AD AR Public db MySql; PMID: 23765059 339 NFIC unknown PBio PMID: 11559801, 15327898, 16928756, 18474555, 19058033, 340 22205750 NFIL3 unknown PBio PMID: 20080759, 20697558, 22075207, 23453631, 24070385, 92 24277151, 24280221, 24442434, 24909887, 25092873, 25113970, 25310240, 25611557, 25614966, 25801035, 25993115, 26153760, 26379372, 26806130, 26880402 NFKB1 AD Public db PMID: 22081022, 26279205 341 NFKB2 AD Public db MySql; PMID: 25764117 342 NFKBIA AD Public db MySql; PMID: 23765059, 25645939, 25764117 343 NHEJ1 AR Public db MySql; PMID: 23765059 344 NLRP12 AD PBio PMID: 17947705, 18230725, 20861596, 21978668, 23318142, 93 23970817, 24282415, 24347638, 25249449, 25620184, 25902475, 26083549, 26343520, 26386126, 26521018 NLRP3 AD Public db PMID: 16724804, 19302049, 23592984, 26848516, 27999438 345 NOD2 AD Public db PMID: 16724804, 19302049, 23584365, 26509073, 26848516, 346 26953272 NQO2 unknown PBio PMID: 16253210, 16905546, 17720881, 18552348, 26046590 94 NRIP1 unknown PBio PMID: 18267075, 23241901, 24969109, 25066731, 25697398, 95 25879677, 26937622 ORAI1 AD AR Public db PMID: 19075015, 20004786, 21790973, 22144678, 23765059, 347 26454313, 26469693 OSTM1 AR Public db PMID: 16813530, 19507210, 21107136, 23685543 348 OVOL2 AD PBio PMID: 16423343, 25267199, 26619963, 26749309 98 PDE3B unknown PBio PMID: 17220874, 23276671, 25816736, 26203135, 26297880, 99 26374610 PDGFRA association PBio PMID: 12660384, 18634583, 18701889, 19246520, 19839938, 100 20032375, 20569695, 21123584, 21975205, 22449623, 22523564, 23771592, 25319708, 25940087 PDSS2 AR PBio PMID: 17186472, 18437205, 18784258, 21567994, 21871565, 101 21983691, 23150520 PGM3 AR Public db MySql; PMID: 25502423 349 PHACTR4 unknown PBio PMID: 15107502, 17609112, 22215804, 22215812, 22766235, 102 23076051, 23203801, 23319639, 24748504, 26850007 PIAS1 unknown PBio PMID: 10805787, 10858346, 14644436, 15297606, 15311277, 103 17065208, 17540171, 18056374, 19857525, 20966256, 22969086, 22982248, 23299081, 24036127 PIAS2 unknown PBio PMID: 9724754, 11117529, 12077349, 12764129, 14514699, 350 15582666, 16460827, 19549844, 21156324, 21779164, 22210188, 22982248, 24344134, 25484205, 25434787, 26223632 PIK3CD AD Both MySql; PMID: 24165795, 25133419, 25645939, 26437962, 104 26453379, 27379089, 27426521, 27873163, 14647476, 27192563 PIK3R1 AD AR Public db PMID: 23765059, 23887241, 25645939, 26246585, 26453379, 351 27076228, 14647476, 27192563 PKHD1 AR PBio PMID: 8178487, 15052665, 17450421, 23423256, 24964219, 105 24984783, 25186187, 26502924 PLCG2 AD Public db PMID: 19056831, 23000145, 23765059, 23887241, 25452106, 352 25636200, 25645939, 26246585, 27192563 PMS2 AR Public db MySql; PMID: 23765059 353 PNPLA4 unknown PBio PMID: 22289388, 23741432, 26017929, 26164793, 26713677, 107 26741492, 26968210 PNPT1 AR PBio PMID: 14563561, 15492272, 16410805, 16687933, 17983748, 108 19580345, 23084291, 23221631, 24143183, 24729470, 25457163 POLA1 XLR Public db PMID: 27019227, 27821552 355 POLE AR Public db MySql; PMID: 23230001, 23765059, 25948378 356 PPP2R3B unknown PBio PMID: 9847399, 10629059, 11593413, 18353419, 20485545, 109 26683421 PRF1 ADAR Public db PMID: 17311987, 19302049, 21881043, 24916509, 25776844, 357 26454313, 26864340, 27391055 PRKCB unknown PBio PMID: 10872892, 15488737, 16935002, 17060474, 17395590, 110 19907441, 21997316, 22994860, 23959874, 24550541, 25548371, 24550541, 25808972, 26509731, 26510741 PRKCD AR Public db MySql; PMID: 23319571, 27250108, 27873163 358 PRKCH unknown PBio PMID: 15327898, 16571806, 18353419, 22114277, 22155788, 111 22892130, 23868949, 24705298, 25617472, 25889880 PRKDC ADAR Public db PMID: 12847277, 23722905, 26454313, 26838362, 27980111 359 PROC ADAR PBio PMID: 2437584, 18751723, 21114396, 22447930, 24162617 360 PSMB8 AR Public db PMID: 26052098, 27260006, 27821552 361 PSTPIP1 AD PBio PMID: 9488710, 11313252, 12530983, 14707117, 16724804, 112 19290936, 19302049, 24421327, 25040622, 25645939, 25814341, 26386126, 26919742 PTEN AD Public db PMID: 26246517, 27426521 362 PTPN2 unknown PBio PMID: 11909529, 12359225, 12847239, 19290937, 19825843, 113 19930043, 20473312, 20564182, 20848498, 21220691, 22080861, 22080863, 22671594, 24442435, 24445916, 24608439, 24849651, 24997008, 25548153, 25581833 PTPRC AR Public db PMID: 26454313 363 PTPRN2 unknown PBio PMID: 9714834, 10426369, 11086001, 11086294, 11793386, 114 15114673, 19361477, 23595248, 24988487, 26141787, 26609326 PURA AD Public db PMID: 27042682 364 RAB27A AR Public db PMID: 19302049, 20008220, 21881043, 23810987 365 RAB37 unknown PBio PMID: 21805469, 22899725, 26931073, 27798165 115 RAB7A AD PMID: 25992615, 27588602 366 RABGEF1 unknown PBio PMID: 12505986, 15143060, 15235600, 16499958, 16533754, 367 16605131, 17341663, 20829437, 22846990, 23552075, 24569883, 24957337, 25427001, 26567216, 26588713, 27791468 RAC2 AD Public db MySql 368 RAD51 AD Public db PMID: 25310191, 27042682 369 RAG2 AR Public db PMID: 23765059, 23887241, 26454313, 27808398 371 RBCK1 AR Public db MySql; PMID: 21455173, 21455181, 23765059, 23969028, 372 24958845, 25764117, 25930993, 26008899, 26525107, 27810922 RBFOX1 unknown PBio PMID: 23350840, 24039908, 25043849, 26500751, 26687839 116 RCC1 unknown PBio PMID: 1961752, 18442486, 19060893, 20347844, 23536659, 117 25452301, 26864624 RFX5 AR Public db PMID: 23765059, 26454313 373 RFXANK AR Public db PMID: 23765059, 26454313 374 RFXAP AR Public db PMID: 23765059, 26454313 375 RGCC unknown PBio PMID: 19158077, 19652095, 23000427, 24973210, 25770350, 118 26134570 RHOQ unknown PBio PMID: 10490598, 12456725, 14734537, 16246732, 17016434, 119 19258391, 22916134, 24223996, 24297911, 24663214, 24667291 RIPK1 association Public db PMID: 21455173, 27999438 376 RIPK3 association Public db PMID:22365665, 27999438 377 RMRP AR Public db MySql; PMID 19782549, 20008220, 24753205 378 RNASE3 unknown PBio PMID: 19515815, 26184157 120 RNASEH2A AR Public db PMID: 26052098, 27260006, 27821552 379 RNASEH2B AR Public db PMID: 26052098, 27260006, 27821552 380 RNASEH2C AR Public db PMID: 26052098, 27260006, 27821552 381 RNASEL association Public db PMID: 24995003, 27525044 382 RNF168 AR Public db MySql; PMID: 23765059 383 RNF31 AR Public db PMID: 21455173, 21455181, 23969028, 24958845, 26008899, 384 26525107, 27810922 RNU4ATAC AR Public db PMID: 27222657 385 RPTOR unknown PBio PMID: 16959881, 22810227, 23349361, 23812589, 24287405, 123 24303063, 24671993, 24948799, 26678875 RTEL1 AR Public db MySql; PMID: 23329068, 23765059, 24009516, 25607374, 386 26810774 RTEL1- unknown Public db MySql; PMID: 23329068, 23765059, 25607374 387 TNFRSF6B SALL2 AR PBio PMID: 11734654, 15082782, 18818376, 19076363, 19131967, 388 21362508, 21689070, 21791360, 22074632, 22978642, 23029531, 24040083, 24412933, 24903482, 25360671, 25580951, 25608837, 26181197 SAMHD1 AR Public db PMID: 26052098, 27260006, 27821552 389 SBDS AR Public db PMID: 20008220, 21062271, 27418648, 27658964 390 SERPINB4 unknown PBio PMID: 15203215, 19070595, 21857942, 22451727, 22808225, 124 24560885, 24635038, 25111616, 25133778, 25213322 SERPINB6 AR PBio PMID: 14670919, 20451170, 24172014, 24359430 125 SH2D1A XLR Public db MySql; PMID: 19302049, 23765059, 25744037 391 SHARPIN unknown Public db PMID: 21455181, 22901541, 23969028, 24958845, 26525107, 392 26848516, 27810922, 27892465 SKIV2L AR Public db PMID: 27260006, 27821552 393 SLC17A5 AR PBio PMID: 14742248, 15006695, 15172005, 16575519, 18399798, 127 20007460, 20951965, 21628664, 22778404, 23760462, 23889254, 25494612, 25855729, 25879139 SLC37A4 AR Public db PMID: 20008220, 20301489 394 SLC3A2 unknown PBio PMID: 22588539, 22624878, 23297381, 24491544, 25002078, 126 26172215, 26439699, 26444422 SLC46A1 AR Public db PMID: 26454313 395 SLC8A1 unknown PBio PMID: 23224883, 23224887, 23224890, 23224891, 26045217, 396 26418956, 26775040, 26859825, 26924806 SMAD2 unknown Public db PMID: 27042682 397 SMAD3 AD Public db PMID: 27042682 398 SMAD4 AD Both PMID: 12202226, 14987161, 16800882, 19420158, 25637015, 399 25705527, 26454313, 27042682 SNAP29 AR Public db PMID: 15968592, 21073448, 27588602 400 SNAR-A1 unknown PBio PMID: 25327818, 25447144 401 SNAR-A10 unknown PBio PMID: 25327818, 25447144 402 SNAR-A11 unknown PBio PMID: 25327818, 25447144 403 SNAR-A12 unknown PBio PMID: 25327818, 25447144 404 SNAR-A13 unknown PBio PMID: 25327818, 25447144 405 SNAR-A14 unknown PBio PMID: 25327818, 25447144 406 SNAR-A2 unknown PBio PMID: 25327818, 25447144 407 SNAR-A3 unknown PBio PMID: 25327818, 25447144 408 SNAR-A4 unknown PBio PMID: 25327818, 25447144 409 SNAR-A5 unknown PBio PMID: 25327818, 25447144 410 SNAR-A6 unknown PBio PMID: 25327818, 25447144 411 SNAR-A7 unknown PBio PMID: 25327818, 25447144 412 SNAR-A8 unknown PBio PMID: 25327818, 25447144 413 SNAR-A9 unknown PBio PMID: 25327818, 25447144 414 SNAR-B1 unknown PBio PMID: 25327818, 25447144 415 SNAR-B2 unknown PBio PMID: 25327818, 25447144 416 SNAR-C1 unknown PBio PMID: 25327818, 25447144 417 SNAR-C2 unknown PBio PMID: 25327818, 25447144 418 SNAR-C3 unknown PBio PMID: 25327818, 25447144 419 SNAR-C4 unknown PBio PMID: 25327818, 25447144 420 SNAR-C5 unknown PBio PMID: 25327818, 25447144 421 SNAR-D unknown PBio PMID: 25327818, 25447144 422 SNAR-E unknown PBio PMID: 25327818, 25447144 423 SNAR-F unknown PBio PMID: 25327818, 25447144 424 SNAR-G1 unknown PBio PMID: 25327818, 25447144 425 SNAR-G2 unknown PBio PMID: 25327818, 25447144 426 SNAR-H unknown PBio PMID: 25327818, 25447144 427 SNAR-I unknown PBio PMID: 25327818, 25447144 428 SNCA AD PBio PMID: 12406186, 14648159, 16953112, 19115126, 19432400, 429 19652146, 22209147, 23378275, 23771222, 24586351, 24593806, 25092570, 25450953, 25522431, 25635231, 25866630, 26087293, 26272943, 26342897, 26646749 SNHG3 unknown PBio PMID: 22308462, 22843687, 26373735 128 SNX10 AR Public db PMID: 22499339, 23123320 430 SNX5 unknown PBio PMID: 10600472, 11128621, 14499622, 15133132, 15561769, 130 16857196, 18596235, 21725319, 21903422, 21943487, 23213485, 24820351, 26220253 SOCS2 unknown PBio PMID: 19279332, 21403007, 22693634, 22795647, 23455506, 131 24400794, 26216515, 26709655, 26765997, 27071013, 27158906, 27330188, 27338192 SP110 AR Public db MySql 431 SP140 unknown Public db MySql 432 SPINK5 AR Public db PMID: 19683336, 26865388, 27222657, 27905021 433 SQSTM1 ADAR Public db PMID: 19229298, 27715390 434 SRSF1 unknown Public db PMID: 27042682 435 ST8SIA5 unknown PBio PMID: 11089916, 15829700 133 STAT2 AR Public db PMID: 23391734, 26122121, 27821552 437 STAT5B AR Public db MySql 439 STIM1 AD AR Public db PMID: 20004786, 21790973, 23765059, 26454313, 26469693 440 STIM2 unknown PBio PMID: 20004786, 21790973, 21880262, 22129055, 22477146, 134 22914293, 25157823, 26109647, 26469693 STK4 AR Public db PMID: 19782549, 23765059, 23887241, 24753205, 26029204 441 STX11 AR Public db PMID: 19302049, 21881043, 24916509, 26454313 442 STXBP2 AD AR Public db PMID: 21881043, 24916509, 25564401, 26454313 443 SYNCRIP unknown PBio PMID: 10734137, 18045242, 19331829, 19232660, 22493061, 444 22935615, 23679954, 23700384, 24844655, 25100733, 26641092 T AD AR PBio PMID: 11897834, 17438107, 23064415, 23662285, 24253444, 445 24556085, 25186612, 26210634, 26919728 TAP1 AR Public db PMID: 26454313 446 TAP2 AR Public db PMID: 26454313 447 TAPBP unknown Public db PMID: 26454313 448 TAZ XLR Public db PMID: 20008220 449 TBC1D16 unknown PBio PMID: 16923123, 19077034, 21250943, 23019362, 23485563, 136 23812537, 24513270, 26030178 TBK1 AD Public db PMID: 23887241, 25930993, 26513235, 28049150 450 TBX1 AD Public db PMID: 26454313 451 TCIRG1 AD AR Public db MySql; PMID 19507210, 19782549, 24753205, 27233968 452 TICAM1 AD AR Public db PMID: 22105173, 23887241, 25764117, 25930993, 26513235, 453 28049150 TLR3 AD Public db PMID: 23592984, 23887241, 25930993, 26513235, 27810922, 454 27873163, 27881733 TLR4 association Both PMID: 12124407, 17893200, 18946062, 19843948, 20521908, 455 21677132, 22474023, 22962435, 23055527, 23890253, 25365308, 25454804, 25930993, 26189680, 26453379, 27881733 TMEM173 AD Public db PMID: 23388631, 25645939, 25692705, 26052098, 27260006, 456 27801882, 27821552 TNF association Public db MySql; PMID: 27042682 457 TNFAIP3 AD Public db PMID: 23969028, 26642243, 27845235 458 TNFRSF10A unknown PBio PMID: 10889508, 11602752, 11704827, 11777550, 11844843, 138 12390973, 12694389, 14975593, 15007095, 16394652, 16554480, 17671142, 19690337, 20921531 TNFRSF11A AD AR Public db PMID: 17088646, 17360404, 18281276, 18606301, 19380800, 459 19507210, 25102334, 25393853, 27003757, 27016605 TNFRSF11B AR Public db PMID: 19507210, 25102334, 25393853, 27003757 460 TNFRSF13B AD AR Public db MySql; PMID: 17467261, 17492055, 18978466, 18981294, 461 19629655, 20889194, 21458042, 22697072, 23765059, 25454804, 25930993, 26727773, 27123465 TNFRSF13C AR Both MySql; PMID: 16769579, 17785824, 18784835, 18813230, 139 19136305, 19406831, 20547827, 20547828, 20817206, 21897850, 22028296, 22030463, 23684423, 24101550, 24953530, 25454804, 25637018, 25724205, 26419927, 26453379, 26600308, 26888554 TNFRSF18 unknown PBio PMID: 16439533, 19162554, 19363449, 22017440, 23432692, 140 24484736, 25738498 TNFRSF4 AR Public db MySql 462 TNFRSF8 unknown PBio PMID: 10921351, 15990453, 16472805, 18852356, 20141444, 463 20378007, 21933041, 23115213, 23307550, 23654079, 24809535, 25999451 TNFSF11 AR Public db PMID: 17088646, 17360404, 18281276, 18606301, 19507210, 464 25992615, 27003757 TNFSF12 association Public db PMID: 23765059 465 TP53 AD AR Public db MySql; PMID: 11048806, 11079782, 12009037, 19282432, 466 26870672 TRAF3 AD Public db PMID: 20832341, 23887241, 25764117, 25930993, 28049150 467 TRAF6 unknown Public db PMID: 10215628, 10421844, 25200954, 27808398, 27999438 468 TRAFD1 unknown PBio PMID: 16221674, 18849341, 23913580, 25909814, 25992615, 141 26283173 TREX1 AD AR Public db PMID: 26052098, 27260006, 27821552 469 TRNT1 AR Public db MySql; PMID: 25193871 470 TRPM2 unknown PBio PMID: 9806837, 16585058, 18569867, 19411837, 20107186, 142 25012489, 25049394, 25088676, 26300888, 26558786, 26679996, 26942016, 26969190, 27405665, 27872485 TTC7A AR Public db MySql; PMID: 27873163 471 UBE2N unknown PBio PMID: 21512573, 23159053, 24906799, 25343992, 25503582, 145 25548215, 26085214, 26150489, 26212332, 26518362 UNC119 AD Public db MySql 472 UNC13D AR Public db PMID: 19302049, 21881043, 24916509, 25564401, 25980904, 473 26454313 UNC93B1 association Public db PMID: 23810987, 23887241, 25930993, 27873163 474 UNG AR Public db MySql; PMID: 23765059 475 USP18 AR Public db PMID: 27016605, 27325888, 27801882, 27821552 476 USP20 unknown Public db PMID: 27801882 477 VAPA unknown PBio PMID: 9657962, 10523508, 10655491, 11511104, 12931207, 478 18713837, 23536298, 24076421, 24569996, 25015719 VCP AD Public db PMID: 24248593, 27730320 479 VDAC1 unknown PBio PMID: 10620603, 25874870, 26322231, 26542804, 26616244, 480 26758954, 26878172 VPS13B AR Public db PMID: 20008220, 20301655 481 VPS45 AR Public db MySql; PMID: 23738510, 24145314, 24164830, 26358756 482 VSTM1 unknown PBio PMID: 22960280, 23436183, 24205237, 25351446, 25887911, 147 26760041 VWA2 unknown PBio PMID: 14506275, 18434322, 21385852, 23443151, 23960233, 148 26121272 WEE1 unknown Public db PMID: 19903823, 25088202, 26598692, 26881506, 27042682 484 WIPF1 AR Public db PMID: 23765059, 26029204, 26453379 485 XIAP XLD XLR Public db MySql; PMID: 22365665, 25744037, 26953272 486 YBX1 unknown Public db PMID: 27042682 487 YWHAZ unknown Both PMID: 25894827, 27042682 488 ZAP70 AD AR Public db PMID: 18219311, 23494777, 23765059, 24164480, 26454313 489 ZBTB24 AR Public db MySql; PMID: 23486536, 23765059, 26851945, 27098601 490

Table 6 is a comprehensive list of 419 exemplary genes (referred to herein as ‘PML-419 genes’ or ‘PML-419 gene list’) interrogated in the present study, along with information related to the inheritance pattern assumed for analysis and the reason for inclusion of the gene. Gene sources for Table 6 (column heading ‘Gene Source’): 1) nominated on the basis of being linked to immune deficiency, as curated from public databases (indicated by ‘Public db’) such as PubMed and ClinVar, 2) PBio CNV-identified genes (‘PBio’, see Table 6 column heading ‘Gene Source’) from a genome-wide array CGH gene discovery study of 71 PML cases, or 3) curated from public databases and identified in PBio's PML gene discovery study (indicated by ‘Both’). A genetic predisposition to PML on the basis of the host's genome was proposed; that is, germline genetic variant(s) in the PML patient's genome, rather than genetic variants that are present in the JC virus, are the cause of the patient's PML (Hatchwell, Front Immunol., 6:216 (2015). Details on the source of the genes in the PML-419 gene list can be found in the following immunodeficiency and immune-related gene sources: Durandy et al., Nat Rev Immunol., 13(7):519-33 (2013); Milner et al., Nat Rev Immunol., 13(9):635-48 (2013); Paciolla et al., Genes Immun., 16(4):239-46 (2015); Hatchwell, Front Immunol., 6:216 (2015); Thijssen et al., Nat Commun., 6:7870 (2015); Chinn et al., Immunol Allergy Clin North Am., 35(4):671-94 (2015); Zhou et al., Nat Genet., 48(1):67-73 (2015); Navabi et al., Allergy Asthma Clin Immunol., 12:27 (2016); and Tsujita et al., J Allergy Clin Immunol. (2016). MySql′ genes are derived from the ClinVar database. ClinVar was searched using the terms “immune deficiency” and “immunodeficiency.” Entries that described large genomic rearrangements, containing multiple genes, were excluded. A non-redundant list of 125 genes was compiled by combining the output of the two searches and deposited into a MySQL database. NOTE: A subset of these genes are not flagged as ‘MySql’ if they appeared in one or more of the immune gene review papers noted above. van der Kolk et al., Ann Clin Transl Neurol.; 3(3):226-32 (2016) was the source of known BAG3 PML gene (see below) and 28 candidate PML genes on the basis of connection to JCV. Van der Kolk et al., cite a method as follows: “the latter was performed by searching for JCV in NCBI, and selecting for genes in humans.” This yielded 30 human genes, 5 of which overlapped with the PML gene list and 2 genes (HLA-DQB1, HLA-DRB1) were excluded because HLA loci are difficult to interpret. The genes ADA, BAG3, BTK, CD40LG, DOCKS, STAT1, WAS, and WIPF1 were derived from Hatchwell, Front Immunol., 6:216 (2015) (see Table 1 for primary references); van der Kolk et al., Ann Clin Transl Neurol., 3(3):226-32 (2016); and Zerbe et al., Clin Infect Dis., 62(8):986-94 (2016). PBio genes are based on CNV studies and a subset overlap the immune review gene lists (annotated as ‘Both’ in column heading ‘Gene Source’). Tier 1 genes were used as potential solutions for PML cases. Determination of Autosomal Dominant (AD), Autosomal Recessive (AR), X-linked dominant (XLD), or X-linked (XLR) disease model for each gene was derived from the immunodeficiency review papers and/or OMIM annotations. Entries marked ‘association’ denotes variants were found to be associated with an immune-related condition; ‘unknown’ denotes no evidence reported in the literature for an AD or AR model.

TABLE 7 Potential cause of PML in each patient in the study Varian Frequency Frequency (Reciprocol) Primary RefSeq Gene Variant Details (Ethnic (Ethnic SEQ SampleID Ethnicity Gender Disease Symbol Type specific) specific ID MVGS1116-8a EUR F MS (NZ Rx) DOCK8 SNV hom 0.499 1 in 1,792 1147 MVGS1359 EUR F MS (NZ Rx) IL17F SNV het 0.00024 1 in 4,170 1114 MVGS1368 EUR F MS (NZ Rx) IDO2 SNV hom 0.508 1 in 121 1125 SNV het 0.065 1126 MVGS540-374b EUR M MS (NZ Rx) SHARPIN SNV hom 0.00217 1 in 461 1142 MVGS540-393b EUR F MS (NZ Rx) DOCK8 SNV hom 0.499 1 in 5,246 1147 SNV het 0.00153 1154 SNV het 0.194 1152 MVGS694-6a EUR F Other CHD7 SNV het 0.00028 1 in 3,528 1135 MVGS811-13a EUR M HIV PIK3CD CNV hom novel 0 2 PIK3CD-AS1 MVGS995-4a EUR M MS (NZ Rx) EPG5 SNV hom 0.495 1 n 32,224 1279 SNV het 0.000251 1273 PML01 EUR F HIV ITSN2 SNV hom 0.00183 1 in 547 1028 PML02 EUR M Other IKBKB SNV het novel 0 1127 PML03 EUR F MS (NZ Rx) FPR2 CNV hom 2.23E−06 1 in 448,833 140 PML04 EUR M HIV unsolved n/a n/a n/a n/a PML05 LAT M HIV TBK1 SNV het novel 0 1203 PML06 AFR M HIV TICAM1 SNV het 0.000777 1 in 1,287 1289 PML09 EUR M HIV LIG4 SNV 0.00399 1 in 3497 1221 SNV comp 0.287 1222 het PML10 EUR F HIV TNFRSF11A SNV het novel 0 1287 PML12 LAT F HIV BLM SNV hom 0.000874 1 in 1,144 1235 PML13 AFR M HIV PLCG2 SNV 0. 00167 1 in 128,105 1261 SNV comp het 0.0187 1263 PML14 EUR M HIV PLCG2 SNV 0.00998 1 in 25,259 1261 SNV comp het 0.0159 1263 PML15 LAT M HIV NOD2 SNV het novel 0 1255 PML16 AFR F HIV TNFRSF11A SNV het novel 0 1287 PML17 EUR M HIV ZAP70 SNV het 0.00009 1 in 11,110 1035 PML18 EUR M HIV unsolved n/a n/a n/a n/a PML19 AFR M HIV ATM SNV 0.0479 0 1193 SNV comp het novel 1194 PML20 AFR M HIV NFKB1 SNV het 0.00173 1 in 577 1069 PML21 EUR M HIV ZAP70 SNV het 0.0000602 1 in 16,623 1034 PML22 EUR M HIV unsolved n/a n/a n/a n/a PML23 EUR F HIV DCLRE1C SNV hom novel 0 1167 PML25 EUR F HIV PLCG2 SNV het 0.000150 1 in 6,672 1259 PML26 EUR M HIV TRAFD1 SNV hom 0.000689 1 in 1,451 1208 PML27 EUR M HIV TAP2 SNV hom 0.00837 1 in 120 1101 PML28 EUR F MS (NZ Rx) TRPM2 SNV hom novel 0 1311 PML29 AFR M HIV KCTD7 CNV hom 0.000387 1 in 2,584 65 RABGEF1 PML30 EUR M HIV TNFRSF11A SNV het novel 0 1287 PML31 AFR F HIV DDX58 SNV het 0.000779 1 in 1,283 1157 PML32 EUR M HIV unsolved n/a n/a n/a n/a PML33 EUR M HIV TNFRSF11A SNV het novel 0 1287 PML35 EUR F HIV TNFRSF11A SNV het novel 0 1287 PML36 AFR F HIV TCIRG1 SNV het 0.002134 1 in 469 1184 PML37 AFR M HIV GATA2 SNV het novel 0 1056 PML38 EUR M HIV MALL CNV hom 3.95E−06 1 in 253,036 26 PML39 AFR M HIV unsolved n/a n/a n/a n/a PML40 LAT F HIV PNPT1 SNV hom novel 0 1032 PML41 AFR M HIV ZAP70 SNV het novel 0 1036 PML43 EUR M HIV PTPRC SNV hom novel 0 1020 PML44 EUR M HIV TNFRSF11A SNV het novel 0 1287 PML45 EUR F Other CARD11 SNV het 0.0024 1 in 417 1123 PML46 LAT M HIV EPG5 SNV 0. 0123 1 in 745 1278 SNV comp het 0.436 1279 PML48 EUR M HIV SMAD4 SNV het 0.000901 1 in 11,100 1284 PML49 EUR M HIV STIM1 SNV het novel 0 1174 PML50 AFR M HIV NOD2 SNV het novel 0 1256 PML51 EUR M HIV TICAM1 SNV het 0.00265 1 in 377 1289 PML52 EUR F Other unsolved n/a n/a n/a n/a PML53 EUR M Other GFI1 SNV het 0.00003 1 in 32,635 1011 PML54 EUR F HIV TNFRSF11A SNV het novel 0 1287 PML55 EUR F HIV RTEL1 SNV het 0.00326 1 in 307 1299 PML56 EUR M HIV TNFRSF11A SNV het novel 0 1287 PML57 EUR F Other TRAF3 SNV het 0.00093 1 in 1,075 1229 PML58 AFR M HIV DOCK8 SNV 0. 0575 1 in 146 1146 SNV comp het 0.478 1147 PML59 AFR M HIV IFIH1 SNV het 0.00281 1 in 356 1040 PML60 EUR M HIV unsolved n/a n/a n/a n/a PML61 AFR F HIV TNFRSF11A SNV het novel 0 1287 PML62 AFR F HIV unsolved n/a n/a n/a n/a PML63 AFR M HIV PLCG2 SNV het 0.00195 1 in 514 1260 PML64 AFR M HIV PIK3R1 SNV het novel 0 1077 PML65 AFR M HIV ITSN2 CNV hom 0.00313 1 in 319 14 PML66 AFR M HIV unsolved n/a n/a n/a n/a PML67 EUR F MS (NZ Rx) unsolved n/a n/a n/a n/a (CNV data, no WES data) PML68 EUR F MS (NZ Rx) LRBA SNV hom 0.00162 1 in 618 1073 PML69 EUR M Other EGR1 ETF1 CNV hom 0.001 1 in 1,005 45 PML72 AFR F HIV NOD2 SNV het 0.004036 1 in 248 1252

Table 7 contains a single genetic solution/explanation that is the potential cause of PML in each patient in the study (71 cases were assessed with genome-wide array CGH and 71 were also assessed by whole exome sequencing), with the exception of 19 ‘unsolved’ cases. Solutions are based on a combination of CNV and SNV variants, connected by SEQ IDs to tables 1, 4 and 5. For homozygous or compound heterozygous variant solutions, expected population frequencies were calculated as follows:

Expected population frequency for variant a (freq p) and variant b (freq q)=pq/4.

For example, PML09 has 2 variants, SEQID 1221 and 1222, with individual frequencies in the normal population of 0.00399, 0.287. The expected frequency in an ethnically-matched normal population for this combination is (0.00399*0.287)*0.25=0.000286283=1/3,497.

The Primary Disease identifiers in Table 7 are: HIV, infection with human immunodeficiency virus; MS (NZ Rx), multiple sclerosis treated with natalizumab; Other, which includes a variety of disorders/conditions (MVGS694-6a had aplastic anemia, PML02 and PML52 had lymphoma, PML45 and PML 57 had chronic lymphocytic leukemia, PML53 had sarcoidosis, and PML69 is a kidney transplant patient who was on belatacept).

Solutions were considered on the basis of presence of rare variants (CNVs and/or SNVs) in or near genes that are listed in Table 6. Both autosomal recessive (AR) and autosomal dominant (AD) disease models comprise this set of solutions, based on finding homozygous SNVs, homozygous CNVs, compound heterozygous SNVs, or heterozygous SNVs. Nine PML cases in Table 7 were considered ‘unsolved’ on the basis of analyzing both CNV and SNV data, and one case (PML67) was assessed for CNVs only since WES data were unavailable. In some instances, a case was considered unsolved for a best solution (Table 7) but alternate solutions were reported in Table 8 (see below).

For PML cases that had more than one potential solution. In these instances, the ‘best’ solution (Table 7) was determined on the basis of rarity of the genetic variant(s) and the relative strength of the biology for the PML-419 genes (Table 6). Alternate solutions are reported in Table 8. For example, for PML case MVGS1116-8a, three solutions were found, which impacted genes DOCK8, HIVEP2, and RNF168. In this example, DOCK8 compound heterozygous SNVs (Table 7, SNV hom and SNV het) were selected as the best solution because DOCK8 is a known PML gene. In another example, PML case MVGS1359 has IL17F (het SNV) listed as the best solution in Table 7 because it is rarer than alternate solutions for the ATR and STXBP2 genes.

While some PML patients may have multiple genes/variants causing and/or contributing to their PML, in many PML patients only a single gene will be the primary cause analogous to patients diagnosed with primary immunodeficiency disorders. In addition to the alternate solutions reported in Table 8, which are based on SNV genetic findings only, additional alternate solutions based on CNV genetic findings are reported in Table 1.

TABLE 8 Alternate genetic solutions/explanations as the potential cause of PML in the study Variant Frequency Frequency RefSeq Gene Details (Reciprocol) Sample ID Symbol Variant Type (Ethnic specific) (Ethnic specific) SEQ ID MVGS1116-8a HIVEP2 SNV het novel 0 1118 MVGS1116-8a RNF168 SNV hom 0.469   1 in 1,041 1063 SNV het 0.00818 1066 MVGS1359 ATR SNV het 0.00393 1 in 254 1058 MVGS1359 STXBP2 SNV het 0.00501 1 in 199 1291 MVGS540-374b MKL1 CNV hom 3.99E−08    1 in 25,081,515 157 MVGS540-393b PRKDC SNV het 0.00097  1 in 1,031 1130 MVGS811-13a CLCN7 SNV het 0.00028  1 in 3,571 1239 MVGS995-4a KAT6B SNV het 0.00003   1 in 33,357 1169 MVGS995-4a PRF1 SNV het 0.00243 1 in 412 1168 PML03 CDKN1B SNV het 0.00003   1 in 32,209 1200 PML05 ATR SNV het novel 0 1061 PML05 NFKB1 SNV het 0.00501 1 in 200 1070 PML06 CHD7 SNV het 0.00797 1 in 125 1136 PML06 DOCK8 SNV hom 0.478  1 in 267 1147 SNV het 0.0313  1152 PML09 RIPK3 SNV het 0.00398 1 in 251 1227 PML10 JUN SNV het 0.00103 1 in 968 1009 PML10 RAG1 SNV het 0.00039  1 in 2,566 1179 PML12 CARD11 SNV het novel 0 1122 PML12 PRKDC SNV het novel 0 1128 PML13 DOCK8 SNV hom 0.478  1 in 267 1147 SNV het 0.0313  1152 PML13 IRAK4 SNV het novel 0 1202 PML13 PIK3CD SNV het 0.00679 1 in 147 1000 PML14 NBN SNV het 0.0039  1 in 256 1138 PML14 NFKB1 SNV het novel 0 1071 PML15 ASH1L SNV Novel 0 1016 SNV comp het 0.0019  1017 PML15 CHD7 SNV het 0.00176 1 in 568 1133 PML15 HIVEP2 SNV het novel 0 1116 PML15 SUM1 SNV het 0.00587 1 in 170 1175 PML16 TBK1 SNV het novel 0 1204 PML16 TLR3 SNV het 0.00136 1 in 738 1076 PML17 APOL1 SNV het 0.0021  1 in 475 1327 PML18 PKHD1 SNV hom 0.498  1 in 171 1104 SNV het 0.0471  1107 PML19 DOCK8 SNV 0.0575  1 in 146 1146 SNV comp het 0.478  1147 PML19 IFIH1 SNV het 0.00444 1 in 225 1041 PML20 JUN SNV het 0.00535 1 in 187 1010 PML21 PRKCH SNV het novel 0 1228 PML21 PSTPIP1 SNV het 0.00093  1 in 1,074 1232 PML21 RAG2 SNV het novel 0 1182 PML22 RIPK3 SNV hom 0.00309 1 in 324 1226 PML22 VPS45 SNV het 0.00114 1 in 878 1014 PML23 NOD2 SNV het novel 0 1251 PML23 RAG1 SNV het 0.00003   1 in 33,317 1180 PML28 PKHD1 SNV hom 0.498  1 in 171 1104 SNV het 0.0471  1107 PML28 INFRSF13B SNV het 0.00929 1 in 108 1267 PML30 RTEL1 SNV het  0.000124  1 in 8,068 1300 PML31 AP3B1 SNV het novel 0 1084 PML31 PRKDC SNV het novel 0 1129 PML33 STIM2 SNV het 0.00003   1 in 32,688 1068 PML33 TLR3 SNV hom 0.413   1 in 2,227 1075 SNV het 0.00435 1074 PML33 TLR4 SNV hom 0.00283 1 in 354 1161 SNV hom 0.00285 1160 PML35 PRKCB SNV het 0.00276 1 in 362 1247 PML36 NOD2 SNV het 0.00871 1 in 115 1254 PML36 PIK3CD SNV het 0.00679 1 in 147 1000 PML37 AP3B1 SNV het novel 0 1080 PML37 ATR SNV het 0.00038  1 in 2,601 1059 PML37 WEE1 SNV het 0.00825 1 in 121 1177 PML38 MYD88 SNV het novel 0 1051 PML40 MCEE SNV hom 0.01   1 in 100 1033 PML41 AP3B1 SNV het 0.00173 1 in 577 1082 PML41 CHD7 SNV het novel 0 1137 PML41 DOCK8 SNV 0.0575  1 in 146 1146 SNV comp het 0.478  1147 PML41 POLE SNV hom 0.00019  1 in 5,203 1219 PML41 RNF168 SNV 0.412  0 1063 SNV comp het novel 1062 PML43 DOCK8 SNV hom 0.499  0 1147 SNV het novel 1150 PML44 DCLRE1C SNV hom 0.0287  1 in 174 1166 SNV hom 0.00575 1165 PML44 GFI1 SNV het 0.00708 1 in 141 1012 PML45 POLA1 SNV het novel 0 1328 PML46 AP3B1 SNV het 0.00587 1 in 170 1082 PML46 IL21R SNV het 0.00573 1 in 175 1248 PML46 PRKDC SNV het 0.00017  1 in 5,781 1131 PML48 TNFRSF11A SNV het 0.00233 1 in 429 1286 PML49 DCLRE1C SNV hom 0.00575 1 in 174 1166 SNV hom 0.0287  1165 PML49 PTEN SNV het novel 0 1171 PML49 RIPK1 SNV het 0.00090  1 in 1,112 1090 PML50 AP3B1 SNV het 0.00387 1 in 259 1078 PML50 PIAS2 SNV het 0.00357 1 in 280 1283 PML50 STXBP2 SNV het 0.00038  1 in 2,598 1290 PML52 GFI1 SNV het 0.00708 1 in 141 1012 PML53 IL1B SNV het novel 0 1037 PML53 STXBP2 SNV het 0.00501 1 in 199 1291 PML54 EPG5 SNV 0.0638  1 in 127 1278 SNV comp het 0.495  1279 PML54 IFNGR2 SNV het 0.00009   1 in 11,096 1304 PML54 RAG1 SNV het 0.00003   1 in 33,352 1178 PML54 RAG2 SNV het novel 0 1183 PML57 PIAS1 SNV het novel 0 1231 PML57 PKHD1 SNV hom 0.498  1 in 171 1104 SNV het 0.0471  1107 PML57 SKIV2L SNV hom 0.157  1 in 538 1098 SNV hom 0.214  1100 SNV het 0.0471  1099 PML58 GFI1 SNV het 0.00144 1 in 693 1012 PML59 IFNLR1 SNV het novel 0 1002 PML59 NOD2 SNV het 0.00404 1 in 248 1252 PML59 NRIP1 SNV hom 0.00711 1 in 141 1301 PML59 RAD51 SNV het 0.00865 1 in 116 1230 PML60 MAPK3 SNV het novel 0 1250 PML60 TP53 SNV het 0.00048  1 in 2,085 1266 PML61 GATA2 SNV het 0.00024  1 in 4,139 1057 PML61 PTPRC SNV hom novel 0 1019 PML61 TNFRSF8 SNV het novel 0 1001 PML62 PRKCD SNV het novel 0 1054 PML63 HTR2A SNV hom 0.00519 1 in 193 1220 PML63 MAPK3 SNV het 0.00193 1 in 518 1249 PML64 PLCG2 SNV het 0.00044  1 in 2,276 1264 PML64 WEE1 SNV het novel 0 1176 PML65 IRAK4 SNV het 0.00118 1 in 850 1201 PML66 PIK3CD SNV het 0.00679 1 in 147 1000 PML68 RAG1 SNV het 0.00586 1 in 171 1181 PML72 CARD11 SNV het 0.00242 1 in 413 1121 PML72 HIVEP1 SNV hom 0.00164 1 in 610 1092 PML72 IFIH1 SNV het 0.00843 1 in 119 1043

Table 8 contains analogous information to Table 7, with the exception that Ethnicity, Gender and Primary Disease are not repeated. Table 8 contains alternate genetic solutions/explanations as the potential cause of PML for the patients in the study (71 cases were assessed with genome-wide array CGH and 70 were also assessed by whole exome sequencing). Solutions in Table 8 are also case-level and represent secondary, alternative solutions for the cases listed (using the same criteria used to identify potential solutions reported in Table 7). In other words, for some individuals, more than one reasonable solution was identified and, while those in Table 7 are considered the most likely, those in Table 8 are also potential solutions. It can be appreciated by those skilled in the art that further data on new PML cases, patients with genetic-based immunodeficiency disorders, or functional studies on a given gene may support selection of a Table 8 solution as the ‘best’ single solution (e.g., a current Table 7 solution could be considered instead as a Table 8 solution, and vice versa).

TABLE 9 Pairs of SNVs impacting the same gene RefSeq Amino Variant Frequency SEQ Gene Variant Ref Alt Acid Details (Ethnic ID Sample ID Symbol Type Chromosome Position Allele Allele Change specific) NO MVGS1359 TTC7A SNV het 2 47273468 A G K252R 0.00684 1030 MVGS1359 TTC7A SNV het 2 47277182 T C S318P 0.00683 1031 MVGS1368 RNF168 SNV het 3 196199204 G T P401Q 0.46947 1063 MVGS1368 RNF168 SNV het 3 196210764 T C n/a 0.00003 1065 MVGS1368 TLR4 SNV het 9 120475302 A G D259G 0.10251 1160 MVGS1368 TLR4 SNV het 9 120475602 C T T3591 0.10560 1161 MVGS811-13a HIVEP1 SNV het 6 12121113 C T P362L 0.00024 1091 MVGS811-13a HIVEP1 SNV het 6 12123538 G T K1170N 0.08730 1093 MVGS995-4a EEA1 SNV het 12 93196332 C T E840K 0.01949 1206 MVGS995-4a EEA1 SNV het 12 93205148 T G E702D 0.00003 1207 PML02 RBFOX1 SNV het 16 7759119 G A G326S 0.00504 1245 PML02 RBFOX1 SNV het 16 7759496 C T P401S novel 1246 PML04 POLE SNV het 12 133220526 T C N1369S 0.22363 1213 PML04 POLE SNV het 12 133237658 T G Q766P novel 1215 PML05 TLR4 SNV het 9 120475302 A G D259G 0.04628 1160 PML05 TLR4 SNV het 9 120475602 C T T359I 0.04180 1161 PML05 POLE SNV het 12 133220526 T C N1369S 0.12669 1213 PML05 POLE SNV het 12 133252406 C A A121S novel 1217 PML10 TLR4 SNV het 9 120475302 A G D259G 0.10251 1160 PML10 TLR4 SNV het 9 120475602 C T T359I 0.10560 1161 PML12 IDO2 SNV het 8 39840234 A G I127V 0.38971 1124 PML12 IDO2 SNV het 8 39862881 C T R235W 0.50282 1125 PML12 IDO2 SNV het 8 39862893 T A S239T 0.02384 1126 PML13 STX11 SNV het 6 144508353 G A V197M novel 1119 PML13 STX11 SNV het 6 144508563 G A V267M 0.00202 1120 PML13 DCLRE1C SNV het 10 14974905 T C H123R 0.16298 1165 PML13 DCLRE1C SNV het 10 14976727 G C P171R 0.22295 1166 PML13 EPG5 SNV het 18 43497710 A G V1058A 0.42740 1279 PML13 EPG5 SNV het 18 43531186 C T S424N 0.00600 1282 PML14 ATM SNV het 11 108117787 C T S333F 0.00280 1188 PML14 ATM SNV het 11 108175462 G A D1853N 0.24654 1193 PML14 TRPM2 SNV het 21 45815425 C G I621M novel 1313 PML14 TRPM2 SNV het 21 45845699 G A V1242M 0.00537 1321 PML16 TLR3 SNV het 4 187004074 C T L135F 0.12378 1075 PML16 TLR3 SNV het 4 187005854 A C I571L 0.00136 1076 PML16 HIVEP1 SNV het 6 12121113 C T P362L 0.07856 1091 PML16 HIVEP1 SNV het 6 12162068 C T S16OF 0.01979 1096 PML16 PKHD1 SNV het 6 51483961 T C Q4048R 0.50029 1104 PML16 PKHD1 SNV het 6 51747943 T A D2433V 0.07153 1112 PML16 POLE SNV het 12 133209020 G C Q2044E novel 1212 PML16 POLE SNV het 12 133220526 T C N1369S 0.24889 1213 PML17 RNF168 SNV het 3 196199204 G T P401Q 0.46947 1063 PML17 RNF168 SNV het 3 196210704 G A P206L 0.00003 1064 PML17 HIVEP1 SNV het 6 12123538 G T K1170N 0.08730 1093 PML17 HIVEP1 SNV het 6 12125232 C T S1735F 0.00027 1095 PML17 PKHD1 SNV het 6 51483961 T C Q4048R 0.49837 1104 PML17 PKHD1 SNV het 6 51497503 C A R3842L 0.04707 1107 PML17 DCLRE1C SNV het 10 14974905 T C H123R 0.27332 1165 PML17 DCLRE1C SNV het 10 14976727 G C P171R 0.13896 1166 PML17 ATM SNV het 11 108119823 T C V410A 0.00643 1189 PML17 ATM SNV het 11 108175462 G A D1853N 0.24654 1193 PML17 EPG5 SNV het 18 43464763 C T G1708D 0.00013 1274 PML17 EPG5 SNV het 18 43497710 A G V1058A 0.49513 1279 PML18 TLR4 SNV het 9 120475302 A G D259G 0.10251 1160 PML18 TLR4 SNV het 9 120475602 C T T3591 0.10560 1161 PML20 AK2 SNV het 1 33476435 C A n/a novel 1003 PML20 AK2 SNV het 1 33478900 T A Y159F 0.04954 1004 PML20 HIVEP1 SNV het 6 12124215 C T P1396L 0.06774 1094 PML20 HIVEP1 SNV het 6 12163657 C T P2374S 0.06733 1097 PML20 KANK1 SNV het 9 711359 C T S198F 0.11985 1155 PML20 KANK1 SNV het 9 713132 G T G631V 0.00136 1156 PML21 DOCK8 SNV het 9 286593 C A P29T 0.49889 1147 PML21 DOCK8 SNV het 9 286593 C A P29T 0.49889 1147 PML21 DOCK8 SNV het 9 312134 G A E169K 0.06358 1149 PML21 DOCK8 SNV het 9 312134 G A E169K 0.06358 1149 PML21 TLR4 SNV het 9 120475302 A G D259G 0.10251 1160 PML21 TLR4 SNV het 9 120475302 A G D259G 0.10251 1160 PML21 TLR4 SNV het 9 120475602 C T T3591 0.10560 1161 PML21 TLR4 SNV het 9 120475602 C T T3591 0.10560 1161 PML21 ATM SNV het 11 108138003 T C F858L 0.02864 1191 PML21 ATM SNV het 11 108138003 T C F858L 0.02864 1191 PML21 ATM SNV het 11 108143456 C G P1054R 0.05069 1192 PML21 ATM SNV het 11 108143456 C G P1054R 0.05069 1192 PML21 TRPM2 SNV het 21 45786650 C T S146F 0.00072 1305 PML21 TRPM2 SNV het 21 45786650 C T S146F 0.00072 1305 PML21 TRPM2 SNV het 21 45820196 C T R735C 0.10374 1314 PML21 TRPM2 SNV het 21 45820196 C T R735C 0.10374 1314 PML22 SKIV2L SNV het 6 31928306 A G Q151R 0.15759 1098 PML22 SKIV2L SNV het 6 31935750 G A V724M 0.04718 1099 PML22 SKIV2L SNV het 6 31936679 C T A1071V 0.21419 1100 PML22 DOCK8 SNV het 9 286593 C A P29T 0.49889 1147 PML22 DOCK8 SNV het 9 304628 G A R151Q 0.00447 1148 PML22 GDPD4 SNV het 11 76954833 G A H383Y 0.44867 1186 PML22 GDPD4 SNV het 11 76979511 A G I233T 0.00504 1187 PML22 ATM SNV het 11 108117787 C T S333F 0.00280 1188 PML22 ATM SNV het 11 108175462 G A D1853N 0.24654 1193 PML22 BLM SNV het 15 91306241 G A R643H 0.00799 1233 PML22 BLM SNV het 15 91341543 A C N1112H novel 1238 PML23 PKHD1 SNV het 6 51483961 T C Q4048R 0.49837 1104 PML23 PKHD1 SNV het 6 51497503 C A R3842L 0.04707 1107 PML23 SHARP1N SNV het 8 145154222 G A P294S 0.08789 1142 PML23 SHARP1N SNV het 8 145154257 C G S282T 0.14880 1144 PML23 DOCK8 SNV het 9 286491 G A D63N 0.27362 1146 PML23 DOCK8 SNV het 9 334277 G A R325H 0.00015 1151 PML25 SKIV2L SNV het 6 31928306 A G Q151R 0.15759 1098 PML25 SKIV2L SNV het 6 31935750 G A V724M 0.04718 1099 PML25 SKIV2L SNV het 6 31936679 C T A1071V 0.21419 1100 PML25 PKHD1 SNV het 6 51483961 T C Q4048R 0.49837 1104 PML25 PKHD1 SNV het 6 51524409 G T S3505R 0.02049 1109 PML25 EPG5 SNV het 18 43445601 T G I174L novel 1270 PML25 EPG5 SNV het 18 43531186 C T S424N 0.02391 1282 PML27 LYST SNV het 1 235897907 C T G2804D 0.00114 1024 PML27 LYST SNV het 1 235909815 A T F165Y 0.00102 1025 PML27 EPG5 SNV het 18 43445601 T G I174L novel 1270 PML27 EPG5 SNV het 18 43497710 A G V1058A 0.49513 1279 PML29 LIG1 SNV het 19 48631258 G A T5461 0.07515 1292 PML29 LIG1 SNV het 19 48639022 T C M412V 0.05385 1293 PML30 DCLRE1C SNV het 10 14974905 T C H123R 0.27332 1165 PML30 DCLRE1C SNV het 10 14976727 G C P171R 0.13896 1166 PML30 ATM SNV het 11 108138003 T C F858L 0.02864 1191 PML30 ATM SNV het 11 108143456 C G P1054R 0.05069 1192 PML30 ATM SNV het 11 108186610 G A G2023R 0.00465 1195 PML31 LYST SNV het 1 235897907 C T G2804D 0.23000 1024 PML31 LYST SNV het 1 235909815 A T F165Y 0.15155 1025 PML31 PKHD1 SNV het 6 51483961 T C Q4048R 0.50029 1104 PML31 PKHD1 SNV het 6 51524339 C G E3529Q 0.07244 1108 PML31 PKHD1 SNV het 6 51747943 T A D2433V 0.07153 1112 PML31 PKHD1 SNV het 6 51798908 C T G2041S 0.00173 1113 PML32 PKHD1 SNV het 6 51483961 T C Q4048R 0.49837 1104 PML32 PKHD1 SNV het 6 51491885 G A Q3899* novel 1106 PML32 EPG5 SNV het 18 43496539 G A S1083L 0.06375 1278 PML32 EPG5 SNV het 18 43497710 A G V1058A 0.49513 1279 PML32 EPG5 SNV het 18 43529551 C T V466M 0.00006 1281 PML33 AK2 SNV het 1 33476435 C A n/a novel 1003 PML33 AK2 SNV het 1 33487007 C T S129N 0.01100 1005 PML33 EPG5 SNV het 18 43497710 A G V1058A 0.49513 1279 PML33 EPG5 SNV het 18 43523240 C T M6101 0.00066 1280 PML35 RNF168 SNV het 3 196199204 G T P401Q 0.46947 1063 PML35 RNF168 SNV het 3 196214320 C T E170K 0.00818 1066 PML36 IDO2 SNV het 8 39862881 C T R235W 0.46108 1125 PML36 IDO2 SNV het 8 39862893 T A S239T 0.01135 1126 PML39 LYST SNV het 1 235897907 C T G2804D 0.23000 1024 PML39 LYST SNV het 1 235909815 A T F165Y 0.15155 1025 PML39 NHEJ1 SNV het 2 219942026 T A Q181L 0.06324 1047 PML39 NHEJ1 SNV het 2 220023045 C T A14T 0.23543 1048 PML40 ATM SNV het 11 108186631 A G 12030V 0.00173 1196 PML40 ATM SNV het 11 108186631 A G 12030V 0.03446 1196 PML40 ATM SNV het 11 108198384 C G L2330V 0.00035 1197 PML40 ATM SNV het 11 108198384 C G L2330V 0.00491 1197 PML41 PKHD1 SNV het 6 51483961 T C Q4048R 0.50029 1104 PML41 PKHD1 SNV het 6 51497503 C A R3842L 0.00654 1107 PML41 IDO2 SNV het 8 39840234 A G I127V 0.06350 1124 PML41 IDO2 SNV het 8 39862881 C T R235W 0.46108 1125 PML45 VPS13B SNV het 8 100791158 G A E2560K 0.00964 1140 PML45 VPS13B SNV het 8 100865941 G A A3442T novel 1141 PML48 EPG5 SNV het 18 43497710 A G V1058A 0.49513 1279 PML48 EPG5 SNV het 18 43531186 C T S424N 0.02391 1282 PML51 TRPM2 SNV het 21 45826486 G A V914I novel 1315 PML51 TRPM2 SNV het 21 45855099 C T R1300W 0.00021 1322 PML53 EPG5 SNV het 18 43445580 C T D181N novel 1269 PML53 EPG5 SNV het 18 43497710 A G V1058A 0.49513 1279 PML56 TLR4 SNV het 9 120475302 A G D259G 0.10251 1160 PML56 TLR4 SNV het 9 120475602 C T T359I 0.10560 1161 PML56 DCLRE1C SNV het 10 14974905 T C H123R 0.27332 1165 PML56 DCLRE1C SNV het 10 14976727 G C P171R 0.13896 1166 PML57 CSF3R SNV het 1 36932047 C T E359K 0.01706 1006 PML57 CSF3R SNV het 1 36933715 A G Y113H 0.00087 1007 PML57 TLR4 SNV het 9 120475302 A G D259G 0.10251 1160 PML57 TLR4 SNV het 9 120475602 C T T359I 0.10560 1161 PML57 ATM SNV het 11 108138003 T C F858L 0.02864 1191 PML57 ATM SNV het 11 108143456 C G P1054R 0.05069 1192 PML57 ATM SNV het 11 108175462 G A D1853N 0.24654 1193 PML58 DOCK8 SNV het 9 399233 A G N1002D 0.19737 1153 PML58 DCLRE1C SNV het 10 14974905 T C H123R 0.16298 1165 PML58 DCLRE1C SNV het 10 14976727 G C P171R 0.22295 1166 PML58 DNMT3B SNV het 20 31383307 G A G311 S 0.00192 1296 PML58 DNMT3B SNV het 20 31384614 G T G343V novel 1297 PML59 LYST SNV het 1 235897907 C T G2804D 0.23000 1024 PML59 LYST SNV het 1 235897907 C T G2804D 0.23000 1024 PML59 LYST SNV het 1 235909815 A T F165Y 0.15155 1025 PML59 LYST SNV het 1 235909815 A T F165Y 0.15155 1025 PML59 LIG1 SNV het 19 48631258 G A T5461 0.07515 1292 PML59 LIG1 SNV het 19 48631258 G A T5461 0.07515 1292 PML59 LIG1 SNV het 19 48639022 T C M412V 0.05385 1293 PML59 LIG1 SNV het 19 48639022 T C M412V 0.05385 1293 PML60 DCLRE1C SNV het 10 14974905 T C H123R 0.27332 1165 PML60 DCLRE1C SNV het 10 14976727 G C P171R 0.13896 1166 PML60 POLE SNV het 12 133202816 C T E2113K 0.04686 1211 PML60 POLE SNV het 12 133220526 T C N1369S 0.22363 1213 PML62 TLR4 SNV het 9 120475302 A G D259G 0.13066 1160 PML62 TLR4 SNV het 9 120475602 C T T3591 0.02672 1161 PML63 HIVEP1 SNV het 6 12124215 C T P1396L 0.06774 1094 PML63 HIVEP1 SNV het 6 12163657 C T P2374S 0.06733 1097 PML63 PLCG2 SNV het 16 81942175 A G N571S 0.01870 1263 PML63 TRPM2 SNV het 21 45795833 G T V297L 0.00097 1306 PML63 TRPM2 SNV het 21 45815307 T C V582A 0.00724 1310 PML64 DNER SNV het 2 230231632 C T D687N 0.00058 1049 PML64 DNER SNV het 2 230450646 T A T259S 0.00692 1050 PML64 IDO2 SNV het 8 39862881 C T R235W 0.46108 1125 PML64 IDO2 SNV het 8 39862893 T A S239T 0.01135 1126 PML65 POLE SNV het 12 133201381 T A I2228F 0.00232 1210 PML65 POLE SNV het 12 133253971 C T R233Q 0.02037 1218 PML66 PKHD1 SNV het 6 51483961 T C Q4048R 0.50029 1104 PML66 PKHD1 SNV het 6 51612746 G A S3223L 0.00000 1110 PML66 PKHD1 SNV het 6 51712759 T C T2641A 0.04812 1111 PML66 EPG5 SNV het 18 43456296 C T R1985Q 0.07733 1271 PML66 EPG5 SNV het 18 43497710 A G V1058A 0.42740 1279 PML68 DCLRE1C SNV het 10 14974905 T C H123R 0.27332 1165 PML68 DCLRE1C SNV het 10 14976727 G C P171R 0.13896 1166 PML72 PSMB8 SNV het 6 32810794 T A T7OS 0.04224 1102 PML72 PSMB8 SNV het 6 32811752 C T G8R 0.04845 1103 PML72 POLE SNV het 12 133220526 T C N1369S 0.24889 1213 PML72 POLE SNV het 12 133245026 G A P477S 0.02332 1216 PML72 RBFOX1 SNV het 16 7568296 C T P102S 0.00692 1242 PML72 RBFOX1 SNV het 16 7703891 A G T235A novel 1243

Table 9 lists, for each case (in multiple rows), variants for which it was not possible, using the whole exome sequencing (WES) data available, to determine phase (e.g., whether two variants are in cis—on the same chromosome—or trans—on opposite chromosomes). Determining phase is an important consideration when dealing with disorders that are being evaluated on an autosomal recessive (AR) basis. If two variants are known to be present but it is impossible to determine whether they are in cis or trans, then it is impossible to conclude that both gene copies are affected, as opposed to only one (albeit with 2 variants). This problem does not arise in the case of homozygous variants, for which it is obvious that the variants must be in trans (e.g., it is only an issue for non-identical variants). All genome coordinates are based on hg19 build.

In summary, Table 9 lists all unphased case-level compound heterozygous SNV solutions, which might represent further case-level solutions, were phasing to have been possible. Furthermore, it can be appreciated by those skilled in the art that unphased solutions reported in Table 9 (2 het SNVs per gene) or Table 10 (see below, which reports het SNVs in patients that also have a CNV reported in Table 1) can potentially cause or contribute to the patient's PML if follow up genetic analysis reveals the pair of variants are on different alleles (e.g., each gene copy impacted by a variant). Variants reported in Tables 1, 9, or 10 may also be found to be significantly deleterious on their own (e.g., in functional studies on patient-derived cells, animal models, etc.) and thus constitute an AD model solution (e.g., genes presently listed as ‘AR’ model in Table 6) may be causal or contributing to disease via an AD or AR model, like several genes already known to be AD or AR (Table 6, ‘AD AR’ disease model).

TABLE 10 SNVs found in genes suspected of being impacted by acquired CNVs RefSeq Amino Variant Frequency SEQ Gene Variant Ref Alt Acid Details (Ethnic ID Sample ID Symbol Type Chr Position Allele Allele Change specific) NO MVGS811- NRIP1 SNV het 21 16338814 T C N567S 0.00060 1301 13a MVGS995- VWA2 SNV het 10 116045796 G A V366M 0.02392 1173 4a PML01 PKHD1 SNV het 6 51497503 C A R3842L 0.04707 1107 PML01 PKHD1 SNV het 6 51483961 T C Q4048R 0.49837 1104 PML02 DUSP16 ¹ SNV het 12 12673965 G A T23M 0.00015 1199 PML39 SALL2 SNV het 14 22004996 G T S13R 0.00231 1225 PML51 JMY SNV het 5 78596018 G C D524H novel 1086 PML65 SALL2 SNV het 14 21992397 T C S347G 0.07709 1223 ¹ The DUSP16 SNV (chr12:12673965) was in trans with a chr12 deletion of DUSP16 in this patient (PML02), whose primary diagnosis was lymphoma.

Table 10 is a list of all heterozygous SNVs that are potentially compound heterozygotes with a CNV on the allele. See text for a fuller explanation. All genome coordinates are based on hg19 build.

TABLE 11 Key that maps Sample ID for the PML cases to the PML Case ID numbers Sample ID PML Case ID MVGS1116-8a 3006 MVGS1359 3117 MVGS1368 3118 MVGS540-374b 3005 MVGS540-393b 3004 MVGS694-6a 3007 MVGS811-13a 3009 MVGS995-4a 3010 PML01 3127 PML02 3126 PML03 3155 PML04 3156 PML05 3125 PML06 3124 PML09 3132 PML10 3157 PML12 3159 PML13 3160 PML14 3161 PML15 3194 PML16 3163 PML17 3140 PML18 3141 PML19 3164 PML20 3143 PML21 3144 PML22 3145 PML23 3165 PML25 3166 PML26 3167 PML27 3168 PML28 3151 PML29 3152 PML30 3153 PML31 3154 PML32 3169 PML33 3170 PML35 3171 PML36 3172 PML37 3173 PML38 3174 PML39 3175 PML40 3273 PML41 3177 PML43 3178 PML44 3179 PML45 3180 PML46 3196 PML48 3197 PML49 3183 PML50 3198 PML51 3185 PML52 3186 PML53 3187 PML54 3188 PML55 3189 PML56 3190 PML57 3191 PML58 3192 PML59 3193 PML60 3199 PML61 3200 PML62 3201 PML63 3202 PML64 3203 PML65 3204 PML66 3205 PML67 3277 PML68 3278 PML69 3279 PML72 3282 PML70 control 3280 PML71 control 3281 PML73 control 3283 PML74 control 3284 PML75 control 3285 PML76 control 3286

Table 11 provides the Sample ID and PML Case ID (experimental ID for CGH data) for 77 ‘PML cases’ (includes 6 non-PML HIV cases listed as controls).

TABLE 12 Non-redundant list of transcript variants that correspond to the set of genes that no CNV ‘solutions’ have been reported in the 71 PML cases RefSeq RefSeq Gene Accession SEQ Symbol Number mRNA Description ID ACADM NM 000016 Homo sapiens acyl-CoA dehydrogenase, C-4 to C-12 straight chain 1500 (ACADM), transcript variant 1, mRNA. ACADM NM 001127328 Homo sapiens atypical chemokine receptor 1 (Duffy blood group) 1501 (ACKR1), transcript variant 1, mRNA. ACKR1 NM 002036 Homo sapiens atypical chemokine receptor 1 (Duffy blood group) 1502 (ACKR1), transcript variant 2, mRNA. ACKR1 NM 001122951 Homo sapiens atypical chemokine receptor 1 isoform a 1503 ACP5 NM 001611 Homo sapiens acid phosphatase 5, tartrate resistant (ACP5), transcript 1504 variant 4, mRNA. ACP5 NM 001111034 Homo sapiens acid phosphatase 5, tartrate resistant (ACP5), transcript 1505 variant 2, mRNA. ACP5 NM 001111035 Homo sapiens acid phosphatase 5, tartrate resistant (ACP5), transcript 1506 variant 1, mRNA. ACP5 NM 001111036 Homo sapiens acid phosphatase 5, tartrate resistant (ACP5), transcript 1507 variant 3, mRNA. ADAR NM 001111 Homo sapiens adenosine deaminase, RNA-specific (ADAR), transcript 1508 variant 1, mRNA. ADAR NM 015840 Homo sapiens adenosine deaminase, RNA-specific (ADAR), transcript 1509 variant 2, mRNA. ADAR NM 015841 Homo sapiens adenosine deaminase, RNA-specific (ADAR), transcript 1510 variant 3, mRNA. ADAR NM 001025107 Homo sapiens adenosine deaminase, RNA-specific (ADAR), transcript 1511 variant 4, mRNA. ADAR NM 001193495 Homo sapiens adenosine deaminase, RNA-specific (ADAR), transcript 1512 variant 5, mRNA. ADK NM 001202450 Homo sapiens adenosine kinase (ADK), transcript variant 4, mRNA. 1513 ADK NM 006721 Homo sapiens adenosine kinase (ADK), transcript variant 2, mRNA. 1514 ADK NM 001123 Homo sapiens adenosine kinase (ADK), transcript variant 1, mRNA. 1515 ADK NM 001202449 Homo sapiens adenosine kinase (ADK), transcript variant 3, mRNA. 1516 AICDA NM 020661 Homo sapiens activation-induced cytidine deaminase (AICDA), mRNA. 1517 AK2 NM 001199199 Homo sapiens adenylate kinase 2 (AK2), transcript variant 3, mRNA. 1518 AK2 NM 013411 Homo sapiens adenylate kinase 2 (AK2), transcript variant 2, mRNA. 1519 AK2 NM 001625 Homo sapiens adenylate kinase 2 (AK2), transcript variant 1, mRNA. 1520 ALG12 NM 024105 Homo sapiens ALG12, alpha-1,6-mannosyltransferase (ALG12), 1521 mRNA. ALPL NM 000478 Homo sapiens alkaline phosphatase, liver/bone/kidney (ALPL), 1522 transcript variant 1, mRNA. ALPL NM 001127501 Homo sapiens alkaline phosphatase, liver/bone/kidney (ALPL), 1523 transcript variant 2, mRNA. ALPL NM 001177520 Homo sapiens alkaline phosphatase, liver/bone/kidney (ALPL), 1524 transcript variant 3, mRNA. AP3B1 NM 001271769 Homo sapiens adaptor related protein complex 3 beta 1 subunit 1525 (AP3B1), transcript variant 2, mRNA. AP3B1 NM 003664 Homo sapiens adaptor related protein complex 3 beta 1 subunit 1526 (AP3B1), transcript variant 1, mRNA. AP3B2 NM 004644 Homo sapiens adaptor-related protein complex 3, beta 2 subunit 1527 (AP3B2), transcript variant 2, mRNA. AP3D1 NM 003938 Homo sapiens adaptor-related protein complex 3, delta 1 subunit 1528 (AP3D1), transcript variant 2, mRNA. AP3D1 NM 001261826 Homo sapiens adaptor-related protein complex 3, delta 1 subunit 1529 (AP3D1), transcript variant 3, mRNA. APOL1 NM 001136540 Homo sapiens apolipoprotein L1 (APOL1), transcript variant 3, mRNA. 1530 APOL1 NM 001136541 Homo sapiens apolipoprotein L1 (APOL1), transcript variant 4, mRNA. 1531 APOL1 NM 003661 Homo sapiens apolipoprotein L1 (APOL1), transcript variant 1, mRNA. 1532 APOL1 NM 145343 Homo sapiens apolipoprotein L1 (APOL1), transcript variant 2, mRNA. 1533 ASH1L NM 018489 Homo sapiens ASH1 like histone lysine methyltransferase (ASH1L), 1534 mRNA. ATL2 NM 001135673 Homo sapiens atlastin GTPase 2 (ATL2), transcript variant 2, mRNA. 1535 ATL2 NM 022374 Homo sapiens atlastin GTPase 2 (ATL2), transcript variant 1, mRNA. 1536 ATL2 NR 024191 Homo sapiens atlastin GTPase 2 (ATL2), transcript variant 3, non- 1537 coding RNA. ATM NM 000051 Homo sapiens ATM serine/threonine kinase (ATM), mRNA. 1538 ATR NM 001184 Homo sapiens ATR serine/threonine kinase (ATR), mRNA. 1539 BACH2 NM 001170794 Homo sapiens BTB domain and CNC homolog 2 (BACH2), transcript 1540 variant 2, mRNA. BACH2 NM 021813 Homo sapiens BTB domain and CNC homolog 2 (BACH2), transcript 1541 variant 1, mRNA. BAG3 NM 004281 Homo sapiens BCL2 associated athanogene 3 (BAG3), mRNA. 1542 BCL10 NM 003921 Homo sapiens B-cell CLL/lymphoma 10 (BCL10), transcript variant 1, 1543 mRNA. BLM NM 000057 Homo sapiens Bloom syndrome RecQ like helicase (BLM), transcript 1544 variant 1, mRNA. BLNK NM 001114094 Homo sapiens B-cell linker (BLNK), transcript variant 2, mRNA. 1545 BLNK NM 001258440 Homo sapiens B-cell linker (BLNK), transcript variant 3, mRNA. 1546 BLNK NM 001258441 Homo sapiens B-cell linker (BLNK), transcript variant 4, mRNA. 1547 BLNK NM 001258442 Homo sapiens B-cell linker (BLNK), transcript variant 5, mRNA. 1548 BLNK NM 013314 Homo sapiens B-cell linker (BLNK), transcript variant 1, mRNA. 1549 BLNK NR 047680 Homo sapiens B-cell linker (BLNK), transcript variant 6, non-coding 1550 RNA. BLNK NR 047681 Homo sapiens B-cell linker (BLNK), transcript variant 7, non-coding 1551 RNA. BLNK NR 047682 Homo sapiens B-cell linker (BLNK), transcript variant 8, non-coding 1552 RNA. BLNK NR 047683 Homo sapiens B-cell linker (BLNK), transcript variant 9, non-coding 1553 RNA. BLOC1S6 NM 012388 Homo sapiens biogenesis of lysosomal organelles complex 1 subunit 6 1554 (BLOC1S6), transcript variant 2, mRNA. BTK NM 000061 Homo sapiens Bruton tyrosine kinase (BTK), transcript variant 1, 1555 mRNA. C11orf65 NM 152587 Homo sapiens chromosome 11 open reading frame 65 (C11orf65), 1556 mRNA. C1QA NM 015991 Homo sapiens complement component 1, q subcomponent, A chain 1557 (C1QA), mRNA. C1QB NM 000491 Homo sapiens complement component 1, q subcomponent, B chain 1558 (C1QB), mRNA. C1QC NM 001114101 Homo sapiens complement component 1, q subcomponent, C chain 1559 (C1QC), transcript variant 1, mRNA. C1QC NM 172369 Homo sapiens complement component 1, q subcomponent, C chain 1560 (C1QC), transcript variant 2, mRNA. C5AR1 NM 001736 Homo sapiens complement component 5a receptor 1 (C5AR1), mRNA. 1561 CARD11 NM 032415 Homo sapiens caspase recruitment domain family member 11 1562 (CARD11), transcript variant 2, mRNA. CARD9 NM 052813 Homo sapiens caspase recruitment domain family, member 9 (CARD9), 1563 transcript variant 1, mRNA. CARD9 NM 052814 Homo sapiens caspase recruitment domain family, member 9 (CARD9), 1564 transcript variant 2, mRNA. CASP8 NM 001080124 Homo sapiens caspase 8 (CASP8), transcript variant F, mRNA. 1565 CASP8 NM 001228 Homo sapiens caspase 8 (CASP8), transcript variant A, mRNA. 1566 CASP8 NM 033355 Homo sapiens caspase 8 (CASP8), transcript variant B, mRNA. 1567 CASP8 NM 033358 Homo sapiens caspase 8 (CASP8), transcript variant E, mRNA. 1568 CASP8 NM 001080125 Homo sapiens caspase 8 (CASP8), transcript variant G, mRNA. 1569 CASP8 NM 033356 Homo sapiens caspase 8 (CASP8), transcript variant C, mRNA. 1570 CCL11 NM 002986 Homo sapiens C-C motif chemokine ligand 11 (CCL11), mRNA. 1571 CCL2 NM 002982 Homo sapiens C-C motif chemokine ligand 2 (CCL2), mRNA. 1572 CCL5 NM 002985 Homo sapiens C-C motif chemokine ligand 5 (CCL5), transcript variant 1573 1, mRNA. CCR2 NM 001123041 Homo sapiens C-C motif chemokine receptor 2 (CCR2), transcript 1574 variant A, mRNA. CCR2 NM 001123396 Homo sapiens C-C motif chemokine receptor 2 (CCR2), transcript 1575 variant B, mRNA. CCR5 NM 000579 Homo sapiens C-C motif chemokine receptor 5 (gene/pseudogene) 1576 (CCR5), transcript variant A, mRNA. CCR5 NM 001100168 Homo sapiens C-C motif chemokine receptor 5 (gene/pseudogene) 1577 (CCR5), transcript variant B, mRNA. CD180 NM 005582 Homo sapiens CD180 molecule (CD180), mRNA. 1578 CD19 NM 001178098 Homo sapiens CD19 molecule (CD19), transcript variant 1, mRNA. 1579 CD19 NM 001770 Homo sapiens CD19 molecule (CD19), transcript variant 2, mRNA. 1580 CD209 NM 001144893 Homo sapiens CD209 molecule (CD209), transcript variant 5, mRNA. 1581 CD209 NM 001144894 Homo sapiens CD209 molecule (CD209), transcript variant 6, mRNA. 1582 CD209 NM 001144895 Homo sapiens CD209 molecule (CD209), transcript variant 7, mRNA. 1583 CD209 NM 001144896 Homo sapiens CD209 molecule (CD209), transcript variant 3, mRNA. 1584 CD209 NM 001144897 Homo sapiens CD209 molecule (CD209), transcript variant 4, mRNA. 1585 CD209 NM 001144899 Homo sapiens CD209 molecule (CD209), transcript variant 8, mRNA. 1586 CD209 NM 021155 Homo sapiens CD209 molecule (CD209), transcript variant 1, mRNA. 1587 CD209 NR 026692 Homo sapiens CD209 molecule (CD209), transcript variant 2, non- 1588 coding RNA. CD247 NM 000734 Homo sapiens CD247 molecule (CD247), transcript variant 2, mRNA. 1589 CD247 NM 198053 Homo sapiens CD247 molecule (CD247), transcript variant 1, mRNA. 1590 CD27 NM 001242 Homo sapiens CD27 molecule (CD27), mRNA. 1591 CD27-AS1 NR 015382 Homo sapiens CD27 antisense RNA 1 (CD27-AS1), long non-coding 1592 RNA. CD34 NM 001025109 Homo sapiens CD34 molecule (CD34), transcript variant 1, mRNA. 1593 CD34 NM 001773 Homo sapiens CD34 molecule (CD34), transcript variant 2, mRNA. 1594 CD3D NM 000732 Homo sapiens CD3d molecule (CD3D), transcript variant 1, mRNA. 1595 CD3D NM 001040651 Homo sapiens CD3d molecule (CD3D), transcript variant 2, mRNA. 1596 CD3E NM 000733 Homo sapiens CD3e molecule (CD3E), mRNA. 1597 CD3G NM 000073 Homo sapiens CD3g molecule (CD3G), mRNA. 1598 CD40 NM 001250 Homo sapiens CD40 molecule (CD40), transcript variant 1, mRNA. 1599 CD40 NM 152854 Homo sapiens CD40 molecule (CD40), transcript variant 2, mRNA. 1600 CD40LG NM 000074 Homo sapiens CD40 ligand (CD40LG), mRNA. 1601 CD55 NM 000574 Homo sapiens CD55 molecule (Cromer blood group) (CD55), transcript 1602 variant 1, mRNA. CD55 NM 001114752 Homo sapiens CD55 molecule (Cromer blood group) (CD55), transcript 1603 variant 2, mRNA. CD59 NM 000611 Homo sapiens CD59 molecule (CD59), transcript variant 2, mRNA. 1604 CD59 NM 001127223 Homo sapiens CD59 molecule (CD59), transcript variant 5, mRNA. 1605 CD59 NM 001127225 Homo sapiens CD59 molecule (CD59), transcript variant 6, mRNA. 1606 CD59 NM 001127226 Homo sapiens CD59 molecule (CD59), transcript variant 7, mRNA. 1607 CD59 NM 001127227 Homo sapiens CD59 molecule (CD59), transcript variant 8, mRNA. 1608 CD59 NM 203329 Homo sapiens CD59 molecule (CD59), transcript variant 3, mRNA. 1609 CD59 NM 203330 Homo sapiens CD59 molecule (CD59), transcript variant 1, mRNA. 1610 CD59 NM 203331 Homo sapiens CD59 molecule (CD59), transcript variant 4, mRNA. 1611 CD79A NM 001783 Homo sapiens CD79a molecule (CD79A), transcript variant 1, mRNA. 1612 CD79A NM 021601 Homo sapiens CD79a molecule (CD79A), transcript variant 2, mRNA. 1613 CD79B NM 000626 Homo sapiens CD79b molecule (CD79B), transcript variant 1, mRNA. 1614 CD79B NM 001039933 Homo sapiens CD79b molecule (CD79B), transcript variant 3, mRNA. 1615 CD79B NM 021602 Homo sapiens CD79b molecule (CD79B), transcript variant 2, mRNA. 1616 CD81 NM 004356 Homo sapiens CD81 molecule (CD81), transcript variant 1, mRNA. 1617 CD8A NM 001145873 Homo sapiens CD8a molecule (CD8A), transcript variant 3, mRNA. 1618 CD8A NM 001768 Homo sapiens CD8a molecule (CD8A), transcript variant 1, mRNA. 1619 CD8A NM 171827 Homo sapiens CD8a molecule (CD8A), transcript variant 2, mRNA. 1620 CD8A NR 027353 Homo sapiens CD8a molecule (CD8A), transcript variant 4, non-coding 1621 RNA. CDCA7 NM 031942 Homo sapiens cell division cycle associated 7 (CDCA7), transcript 1622 variant 1, mRNA. CDCA7 NM 145810 Homo sapiens cell division cycle associated 7 (CDCA7), transcript 1623 variant 2, mRNA. CEBPB NM 005194 Homo sapiens CCAAT/enhancer binding protein beta (CEBPB), 1624 transcript variant 1, mRNA. CHD7 NM 017780 Homo sapiens chromodomain helicase DNA binding protein 7 (CHD7), 1625 transcript variant 1, mRNA. CHEK1 NM 001114121 Homo sapiens checkpoint kinase 1 (CHEK1), transcript variant 2, 1626 mRNA. CHEK1 NM 001114122 Homo sapiens checkpoint kinase 1 (CHEK1), transcript variant 1, 1627 mRNA. CHEK1 NM 001244846 Homo sapiens checkpoint kinase 1 (CHEK1), transcript variant 4, 1628 mRNA. CHEK1 NR 045204 Homo sapiens checkpoint kinase 1 (CHEK1), transcript variant 5, non- 1629 coding RNA. CHEK1 NR 045205 Homo sapiens checkpoint kinase 1 (CHEK1), transcript variant 6, non- 1630 coding RNA. CHEK1 NM 001274 Homo sapiens checkpoint kinase 1 (CHEK1), transcript variant 3, 1631 mRNA. CIITA NM 000246 Homo sapiens class II major histocompatibility complex transactivator 1632 (CIITA), transcript variant 2, mRNA. CLCN7 NM 001114331 Homo sapiens chloride channel, voltage-sensitive 7 (CLCN7), transcript 1633 variant 2, mRNA. CLCN7 NM 001287 Homo sapiens chloride channel, voltage-sensitive 7 (CLCN7), transcript 1634 variant 1, mRNA. COG6 NM 001145079 Homo sapiens component of oligomeric golgi complex 6 (COG6), 1635 transcript variant 2, mRNA. COG6 NM 020751 Homo sapiens component of oligomeric golgi complex 6 (COG6), 1636 transcript variant 1, mRNA. COG6 NR 026745 Homo sapiens component of oligomeric golgi complex 6 (COG6), 1637 transcript variant 3, non-coding RNA. CORO1A NM 001193333 Homo sapiens coronin 1A (CORO1A), transcript variant 1, mRNA. 1638 CORO1A NM 007074 Homo sapiens coronin 1A (CORO1A), transcript variant 2, mRNA. 1639 CR2 NM 001006658 Homo sapiens complement component 3d receptor 2 (CR2), transcript 1640 variant 1, mRNA. CR2 NM 001877 Homo sapiens complement component 3d receptor 2 (CR2), transcript 1641 variant 2, mRNA. CRTC3 NM 001042574 Homo sapiens CREB regulated transcription coactivator 3 (CRTC3), 1642 transcript variant 2, mRNA. CRTC3 NM 022769 Homo sapiens CREB regulated transcription coactivator 3 (CRTC3), 1643 transcript variant 1, mRNA. CSF3R NM 000760 Homo sapiens colony stimulating factor 3 receptor (granulocyte) 1644 (CSF3R), transcript variant 1, mRNA. CSF3R NM 156039 Homo sapiens colony stimulating factor 3 receptor (granulocyte) 1645 (CSF3R), transcript variant 3, mRNA. CSF3R NM 172313 Homo sapiens colony stimulating factor 3 receptor (granulocyte) 1646 (CSF3R), transcript variant 4, mRNA. CTLA4 NM 005214 Homo sapiens cytotoxic T-lymphocyte-associated protein 4 (CTLA4), 1647 transcript variant 1, mRNA. CTLA4 NM 001037631 Homo sapiens cytotoxic T-lymphocyte-associated protein 4 (CTLA4), 1648 transcript variant 2, mRNA. CTPS1 NM 001905 Homo sapiens CTP synthase 1 (CTPS1), transcript variant 1, mRNA. 1649 CTSC NM 148170 Homo sapiens cathepsin C (CTSC), transcript variant 2, mRNA. 1650 CTSC NM 001114173 Homo sapiens cathepsin C (CTSC), transcript variant 3, mRNA. 1651 CTSC NM 001814 Homo sapiens cathepsin C (CTSC), transcript variant 1, mRNA. 1652 CX3CR1 NM 001171171 Homo sapiens C-X3-C motif chemokine receptor 1 (CX3CR1), 1653 transcript variant 2, mRNA. CX3CR1 NM 001171172 Homo sapiens C-X3-C motif chemokine receptor 1 (CX3CR1), 1654 transcript variant 3, mRNA. CX3CR1 NM 001171174 Homo sapiens C-X3-C motif chemokine receptor 1 (CX3CR1), 1655 transcript variant 1, mRNA. CX3CR1 NM 001337 Homo sapiens C-X3-C motif chemokine receptor 1 (CX3CR1), 1656 transcript variant 4, mRNA. CXCL12 NM 000609 Homo sapiens C-X-C motif chemokine ligand 12 (CXCL12), transcript 1657 variant 2, mRNA. CXCL12 NM 001033886 Homo sapiens C-X-C motif chemokine ligand 12 (CXCL12), transcript 1658 variant 3, mRNA. CXCL12 NM 001178134 Homo sapiens C-X-C motif chemokine ligand 12 (CXCL12), transcript 1659 variant 4, mRNA. CXCL12 NM 199168 Homo sapiens C-X-C motif chemokine ligand 12 (CXCL12), transcript 1660 variant 1, mRNA. CXCL9 NM 002416 Homo sapiens C-X-C motif chemokine ligand 9 (CXCL9), mRNA. 1661 CXCR1 NM 000634 Homo sapiens C-X-C motif chemokine receptor 1 (CXCR1), mRNA. 1662 CXCR4 NM 001008540 Homo sapiens C-X-C motif chemokine receptor 4 (CXCR4), transcript 1663 variant 1, mRNA. CXCR4 NM 003467 Homo sapiens C-X-C motif chemokine receptor 4 (CXCR4), transcript 1664 variant 2, mRNA. CXorf40A NM 001171907 Homo sapiens chromosome X open reading frame 40A (CXorf40A), 1665 transcript variant 2, mRNA. CXorf40A NM 001171908 Homo sapiens chromosome X open reading frame 40A (CXorf40A), 1666 transcript variant 3, mRNA. CXorf40A NM 178124 Homo sapiens chromosome X open reading frame 40A (CXorf40A), 1667 transcript variant 1, mRNA. CXorf40A NM 001171909 Homo sapiens chromosome X open reading frame 40A (CXorf40A), 1668 transcript variant 4, mRNA. CYBB NM 000397 Homo sapiens cytochrome b-245, beta polypeptide (CYBB), mRNA. 1669 CYP2S1 NM 030622 Homo sapiens cytochrome P450 family 2 subfamily S member 1 1670 (CYP2S1), mRNA. DCLRE1C NM 001033855 Homo sapiens DNA cross-link repair 1C (DCLRE1C), transcript variant 1671 a, mRNA. DCLRE1C NM 001033857 Homo sapiens DNA cross-link repair 1C (DCLRE1C), transcript variant 1672 d, mRNA. DCLRE1C NM 001033858 Homo sapiens DNA cross-link repair 1C (DCLRE1C), transcript variant 1673 c, mRNA. DCLRE1C NM 022487 Homo sapiens DNA cross-link repair 1C (DCLRE1C), transcript variant 1674 b, mRNA. DDX1 NM 004939 Homo sapiens DEAD/H-box helicase 1 (DDX1), mRNA. 1675 DDX58 NM 014314 Homo sapiens DEAD (Asp-Glu-Ala-Asp) box polypeptide 58 1676 (DDX58), mRNA. DHX58 NM 024119 Homo sapiens DEXH (Asp-Glu-X-His) box polypeptide 58 (DHX58), 1677 mRNA. DKC1 NM 001142463 Homo sapiens dyskerin pseudouridine synthase 1 (DKC1), transcript 1678 variant 2, mRNA. DKC1 NM 001363 Homo sapiens dyskerin pseudouridine synthase 1 (DKC1), transcript 1679 variant 1, mRNA. DNMT3B NM 001207055 Homo sapiens DNA methyltransferase 3 beta (DNMT3B), transcript 1680 variant 7, mRNA. DNMT3B NM 001207056 Homo sapiens DNA methyltransferase 3 beta (DNMT3B), transcript 1681 variant 8, mRNA. DNMT3B NM 006892 Homo sapiens DNA methyltransferase 3 beta (DNMT3B), transcript 1682 variant 1, mRNA. DNMT3B NM 175848 Homo sapiens DNA methyltransferase 3 beta (DNMT3B), transcript 1683 variant 2, mRNA. DNMT3B NM 175849 Homo sapiens DNA methyltransferase 3 beta (DNMT3B), transcript 1684 variant 3, mRNA. DNMT3B NM 175850 Homo sapiens DNA methyltransferase 3 beta (DNMT3B), transcript 1685 variant 6, mRNA. DOCK2 NM 004946 Homo sapiens dedicator of cytokinesis 2 (DOCK2), mRNA. 1686 DOCK8 NM 203447 Homo sapiens dedicator of cytokinesis 8 (DOCK8), transcript variant 1, 1687 mRNA. DOCK8 NM 001190458 Homo sapiens dedicator of cytokinesis 8 (DOCK8), transcript variant 2, 1688 mRNA. DOCK8 NM 001193536 Homo sapiens dedicator of cytokinesis 8 (DOCK8), transcript variant 3, 1689 mRNA. DSC1 NM 004948 Homo sapiens desmocollin 1 (DSC1), transcript variant Dsc1b, mRNA. 1690 DSC1 NM 024421 Homo sapiens desmocollin 1 (DSC1), transcript variant Dsc1a, mRNA. 1691 EGR1 NM 001964 Homo sapiens early growth response 1 (EGR1), mRNA. 1692 ELANE NM 001972 Homo sapiens elastase, neutrophil expressed (ELANE), mRNA. 1693 EPG5 NM 020964 Homo sapiens ectopic P-granules autophagy protein 5 homolog (EPG5), 1694 mRNA. ETF1 NM 004730 Homo sapiens eukaryotic translation termination factor 1 (ETF1), 1695 transcript variant 1, mRNA. F9 NM 000133 Homo sapiens coagulation factor IX (F9), transcript variant 1, mRNA. 1696 FAS NM 000043 Homo sapiens Fas cell surface death receptor (FAS), transcript variant 1697 1, mRNA. FAS NM 152871 Homo sapiens Fas cell surface death receptor (FAS), transcript variant 1698 2, mRNA. FAS NM 152872 Homo sapiens Fas cell surface death receptor (FAS), transcript variant 1699 3, mRNA. FAS NR 028033 Homo sapiens Fas cell surface death receptor (FAS), transcript variant 1700 4, non-coding RNA. FAS NR 028034 Homo sapiens Fas cell surface death receptor (FAS), transcript variant 1701 5, non-coding RNA. FAS NR 028035 Homo sapiens Fas cell surface death receptor (FAS), transcript variant 1702 6, non-coding RNA. FAS NR 028036 Homo sapiens Fas cell surface death receptor (FAS), transcript variant 1703 7, non-coding RNA. FASLG NM 000639 Homo sapiens Fas ligand (INF superfamily, member 6) (FASLG), 1704 mRNA. FCGR2A NM 001136219 Homo sapiens Fc fragment of IgG receptor IIa (FCGR2A), transcript 1705 variant 1, mRNA. FCGR2A NM 021642 Homo sapiens Fc fragment of IgG receptor IIa (FCGR2A), transcript 1706 variant 2, mRNA. FCGR3A NM 000569 Homo sapiens Fc fragment of IgG receptor IIIa (FCGR3A), transcript 1707 variant 1, mRNA. FCGR3A NM 001127592 Homo sapiens Fc fragment of IgG receptor IIIa (FCGR3A), transcript 1708 variant 2, mRNA. FCGR3A NM 001127593 Homo sapiens Fc fragment of IgG receptor IIIa (FCGR3A), transcript 1709 variant 3, mRNA. FCGR3A NM 001127595 Homo sapiens Fc fragment of IgG receptor IIIa (FCGR3A), transcript 1710 variant 4, mRNA. FCGR3A NM 001127596 Homo sapiens Fc fragment of IgG receptor IIIa (FCGR3A), transcript 1711 variant 5, mRNA. FCN3 NM 003665 Homo sapiens ficolin 3 (FCN3), transcript variant 1, mRNA. 1712 FCN3 NM 173452 Homo sapiens ficolin 3 (FCN3), transcript variant 2, mRNA. 1713 FEZ1 NM 005103 Homo sapiens fasciculation and elongation protein zeta 1 (FEZ1), 1714 transcript variant 1, mRNA. FEZ1 NM 022549 Homo sapiens fasciculation and elongation protein zeta 1 (FEZ1), 1715 transcript variant 2, mRNA. FOS NM 005252 Homo sapiens Fos proto-oncogene, AP-1 transcription factor subunit 1716 (FOS), mRNA. FOXH1 NM 003923 Homo sapiens forkhead box H1 (FOXH1), mRNA. 1717 FOXN1 NM 003593 Homo sapiens forkhead box N1 (FOXN1), mRNA. 1718 FOXP3 NM 001114377 Homo sapiens forkhead box P3 (FOXP3), transcript variant 2, mRNA. 1719 FOXP3 NM 014009 Homo sapiens forkhead box P3 (FOXP3), transcript variant 1, mRNA. 1720 FPR1 NM 001193306 Homo sapiens formyl peptide receptor 1 (FPR1), transcript variant 1, 1721 mRNA. FPR1 NM 002029 Homo sapiens formyl peptide receptor 1 (FPR1), transcript variant 2, 1722 mRNA. G6PC3 NM 138387 Homo sapiens glucose 6 phosphatase, catalytic, 3 (G6PC3), transcript 1723 variant 1, mRNA. G6PC3 NR 028582 Homo sapiens glucose 6 phosphatase, catalytic, 3 (G6PC3), transcript 1724 variant 2, non-coding RNA. G6PC3 NR 028581 Homo sapiens glucose 6 phosphatase, catalytic, 3 (G6PC3), transcript 1725 variant 3, non-coding RNA. GATA2 NM 001145661 Homo sapiens GATA binding protein 2 (GATA2), transcript variant 1, 1726 mRNA. GATA2 NM 001145662 Homo sapiens GATA binding protein 2 (GATA2), transcript variant 3, 1727 mRNA. GATA2 NM 032638 Homo sapiens GATA binding protein 2 (GATA2), transcript variant 2, 1728 mRNA. GFI1 NM 005263 Homo sapiens growth factor independent 1 transcription repressor 1729 (GFI1), transcript variant 1, mRNA. GFI1 NM 001127215 Homo sapiens growth factor independent 1 transcription repressor 1730 (GFI1), transcript variant 2, mRNA. GFI1 NM 001127216 Homo sapiens growth factor independent 1 transcription repressor 1731 (GFI1), transcript variant 3, mRNA. GOLGB1 NM 001256486 Homo sapiens golgin B1 (GOLGB1), transcript variant 1, mRNA. 1732 GOLGB1 NM 001256487 Homo sapiens golgin B1 (GOLGB1), transcript variant 3, mRNA. 1733 GOLGB1 NM 001256488 Homo sapiens golgin B1 (GOLGB1), transcript variant 4, mRNA. 1734 GOLGB1 NM 004487 Homo sapiens golgin B1 (GOLGB1), transcript variant 2, mRNA. 1735 GPRC5A NM 003979 Homo sapiens G protein-coupled receptor class C group 5 member A 1736 (GPRC5A), mRNA. GRAP2 NM 004810 Homo sapiens GRB2-related adaptor protein 2 (GRAP2), mRNA. 1737 HAX1 NM 006118 Homo sapiens HCLS1 associated protein X-1 (HAX1), transcript 1738 variant 1, mRNA. HAX1 NM 001018837 Homo sapiens HCLS1 associated protein X-1 (HAX1), transcript 1739 variant 2, mRNA. HELLS NM 018063 Homo sapiens helicase, lymphoid-specific (HELLS), transcript variant 1740 1, mRNA. HIVEP1 NM 002114 Homo sapiens human immunodeficiency virus type I enhancer binding 1741 protein 1 (HIVEP1), mRNA. HIVEP2 NM 006734 Homo sapiens human immunodeficiency virus type I enhancer binding 1742 protein 2 (HIVEP2), mRNA. HIVEP3 NM 001127714 Homo sapiens human immunodeficiency virus type I enhancer binding 1743 protein 3 (HIVEP3), transcript variant 2, mRNA. HIVEP3 NM 024503 Homo sapiens human immunodeficiency virus type I enhancer binding 1744 protein 3 (HIVEP3), transcript variant 1, mRNA. HIVEP3 NR 038260 Homo sapiens human immunodeficiency virus type I enhancer binding 1745 protein 3 (HIVEP3), transcript variant 3, non-coding RNA. HIVEP3 NR 038261 Homo sapiens human immunodeficiency virus type I enhancer binding 1746 protein 3 (HIVEP3), transcript variant 4, non-coding RNA. HP NM 001126102 Homo sapiens haptoglobin (HP), transcript variant 2, mRNA. 1747 HP NM 005143 Homo sapiens haptoglobin (HP), transcript variant 1, mRNA. 1748 HPCAL1 NM 002149 Homo sapiens hippocalcin like 1 (HPCAL1), transcript variant 1, 1749 mRNA. HPCAL1 NM 134421 Homo sapiens hippocalcin like 1 (HPCAL1), transcript variant 2, 1750 mRNA. HPCAL1 NM 001258357 Homo sapiens hippocalcin like 1 (HPCAL1), transcript variant 3, 1751 mRNA. HPCAL1 NM 001258358 Homo sapiens hippocalcin like 1 (HPCAL1), transcript variant 4, 1752 mRNA. HPCAL1 NM 001258359 Homo sapiens hippocalcin like 1 (HPCAL1), transcript variant 5, 1753 mRNA. HTR2A NM 000621 Homo sapiens 5-hydroxytryptamine receptor 2A (HTR2A), transcript 1754 variant 1, mRNA. HTR2A NM 001165947 Homo sapiens 5-hydroxytryptamine (serotonin) receptor 2A, G protein- 1755 coupled (HTR2A), transcript variant 2, mRNA. ICOS NM 012092 Homo sapiens inducible T-cell costimulator (ICOS), mRNA. 1756 IDI1 NM 004508 Homo sapiens isopentenyl-diphosphate delta isomerase 1 (IDI1), 1757 transcript variant 1, mRNA. IFIH1 NM 022168 Homo sapiens interferon induced with helicase C domain 1 (IFIH1), 1758 mRNA. IFNAR1 NM 000629 Homo sapiens interferon (alpha, beta and omega) receptor 1 (IFNAR1), 1759 mRNA. IFNAR2 NM 207584 Homo sapiens interferon (alpha, beta and omega) receptor 2 (IFNAR2), 1760 transcript variant 3, mRNA. IFNAR2 NM 207585 Homo sapiens interferon (alpha, beta and omega) receptor 2 (IFNAR2), 1761 transcript variant 1, mRNA. IFNAR2 NM 000874 Homo sapiens interferon (alpha, beta and omega) receptor 2 (IFNAR2), 1762 transcript variant 2, mRNA. IFNG NM 000619 Homo sapiens interferon gamma (IFNG), mRNA. 1763 IFNGR1 NM 000416 Homo sapiens interferon gamma receptor 1 (IFNGR1), mRNA. 1764 IFNGR2 NM 005534 Homo sapiens interferon gamma receptor 2 (interferon gamma 1765 transducer 1) (IFNGR2), transcript variant 2, mRNA. IGLL1 NM 020070 Homo sapiens immunoglobulin lambda like polypeptide 1 (IGLL1), 1766 transcript variant 1, mRNA. IGLL1 NM 152855 Homo sapiens immunoglobulin lambda like polypeptide 1 (IGLL1), 1767 transcript variant 2, mRNA. IKBKB NM 001190720 Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B- 1768 cells, kinase beta (IKBKB), transcript variant 2, mRNA. IKBKB NM 001242778 Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B- 1769 cells, kinase beta (IKBKB), transcript variant 7, mRNA. IKBKB NM 001556 Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B- 1770 cells, kinase beta (IKBKB), transcript variant 1, mRNA. IKBKB NR 033818 Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B- 1771 cells, kinase beta (IKBKB), transcript variant 5, non-coding RNA. IKBKB NR 033819 Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B- 1772 cells, kinase beta (IKBKB), transcript variant 6, non-coding RNA. IKBKB NR 040009 Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B- 1773 cells, kinase beta (IKBKB), transcript variant 8, non-coding RNA. IKBKG NM 001099856 Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B- 1774 cells, kinase gamma (IKBKG), transcript variant 2, mRNA. IKBKG NM 001099857 Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B- 1775 cells, kinase gamma (IKBKG), transcript variant 1, mRNA. IKBKG NM 001145255 Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B- 1776 cells, kinase gamma (IKBKG), transcript variant 4, mRNA. IKBKG NM 003639 Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B- 1777 cells, kinase gamma (IKBKG), transcript variant 3, mRNA. IKZF1 NM 001220765 Homo sapiens IKAROS family zinc finger 1 (IKZF1), transcript variant 1778 2, mRNA. IKZF1 NM 001220767 Homo sapiens IKAROS family zinc finger 1 (IKZF1), transcript variant 1779 4, mRNA. IKZF1 NM 001220768 Homo sapiens IKAROS family zinc finger 1 (IKZF1), transcript variant 1780 5, mRNA. IKZF1 NM 001220770 Homo sapiens IKAROS family zinc finger 1 (IKZF1), transcript variant 1781 7, mRNA. IKZF1 NM 001220771 Homo sapiens IKAROS family zinc finger 1 (IKZF1), transcript variant 1782 8, mRNA. IKZF1 NM 006060 Homo sapiens IKAROS family zinc finger 1 (IKZF1), transcript variant 1783 1, mRNA. IL10 NM 000572 Homo sapiens interleukin 10 (IL10), mRNA. 1784 IL10RA NM 001558 Homo sapiens interleukin 10 receptor subunit alpha (IL10RA), 1785 transcript variant 1, mRNA. IL10RA NR 026691 Homo sapiens interleukin 10 receptor subunit alpha (IL10RA), 1786 transcript variant 2, non-coding RNA. IL10RB NM 000628 Homo sapiens interleukin 10 receptor subunit beta (IL10RB), mRNA. 1787 IL12B NM 002187 Homo sapiens interleukin 12B (IL12B), mRNA. 1788 IL12RB1 NM 005535 Homo sapiens interleukin 12 receptor subunit beta 1 (IL12RB1), 1789 transcript variant 1, mRNA. IL12RB1 NM 153701 Homo sapiens interleukin 12 receptor subunit beta 1 (IL12RB1), 1790 transcript variant 2, mRNA. IL17F NM 052872 Homo sapiens interleukin 17F (IL17F), mRNA. 1791 IL17RA NM 014339 Homo sapiens interleukin 17 receptor A (IL17RA), transcript variant 1, 1792 mRNA. IL1B NM 000576 Homo sapiens interleukin 1, beta (IL1B), mRNA. 1793 IL21 NM 001207006 Homo sapiens interleukin 21 (IL21), transcript variant 2, mRNA. 1794 IL21 NM 021803 Homo sapiens interleukin 21 (IL21), transcript variant 1, mRNA. 1795 IL21R NM 181078 Homo sapiens interleukin 21 receptor (IL21R), transcript variant 2, 1796 mRNA. IL21R NM 181079 Homo sapiens interleukin 21 receptor (IL21R), transcript variant 3, 1797 mRNA. IL21R NM 021798 Homo sapiens interleukin 21 receptor (IL21R), transcript variant 1, 1798 mRNA. IL2RA NM 000417 Homo sapiens interleukin 2 receptor, alpha (IL2RA), transcript variant 1799 1, mRNA. IL2RG NM 000206 Homo sapiens interleukin 2 receptor subunit gamma (IL2RG), mRNA. 1800 IL4R NM 000418 Homo sapiens interleukin 4 receptor (IL4R), transcript variant 1, 1801 mRNA. IL4R NM 001257406 Homo sapiens interleukin 4 receptor (IL4R), transcript variant 3, 1802 mRNA. IL4R NM 001257407 Homo sapiens interleukin 4 receptor (IL4R), transcript variant 4, 1803 mRNA. IL4R NM 001257997 Homo sapiens interleukin 4 receptor (IL4R), transcript variant 5, 1804 mRNA. IL7 NM 000880 Homo sapiens interleukin 7 (IL7), transcript variant 1, mRNA. 1805 IL7 NM 001199886 Homo sapiens interleukin 7 (IL7), transcript variant 2, mRNA. 1806 IL7 NM 001199887 Homo sapiens interleukin 7 (IL7), transcript variant 3, mRNA. 1807 IL7 NM 001199888 Homo sapiens interleukin 7 (IL7), transcript variant 4, mRNA. 1808 IL7R NM 002185 Homo sapiens interleukin 7 receptor (IL7R), transcript variant 1, 1809 mRNA. IRAK4 NM 001114182 Homo sapiens interleukin 1 receptor associated kinase 4 (IRAK4), 1810 transcript variant 1, mRNA. IRAK4 NM 001145256 Homo sapiens interleukin 1 receptor associated kinase 4 (IRAK4), 1811 transcript variant 3, mRNA. IRAK4 NM 001145257 Homo sapiens interleukin 1 receptor associated kinase 4 (IRAK4), 1812 transcript variant 4, mRNA. IRAK4 NM 001145258 Homo sapiens interleukin 1 receptor associated kinase 4 (IRAK4), 1813 transcript variant 5, mRNA. IRAK4 NM 016123 Homo sapiens interleukin 1 receptor associated kinase 4 (IRAK4), 1814 transcript variant 2, mRNA. IRF3 NM 001197122 Homo sapiens interferon regulatory factor 3 (IRF3), transcript variant 2, 1815 mRNA. IRF3 NM 001197123 Homo sapiens interferon regulatory factor 3 (IRF3), transcript variant 3, 1816 mRNA. IRF3 NM 001197124 Homo sapiens interferon regulatory factor 3 (IRF3), transcript variant 4, 1817 mRNA. IRF3 NM 001197125 Homo sapiens interferon regulatory factor 3 (IRF3), transcript variant 5, 1818 mRNA. IRF3 NM 001197126 Homo sapiens interferon regulatory factor 3 (IRF3), transcript variant 6, 1819 mRNA. IRF3 NM 001197127 Homo sapiens interferon regulatory factor 3 (IRF3), transcript variant 7, 1820 mRNA. IRF3 NM 001197128 Homo sapiens interferon regulatory factor 3 (IRF3), transcript variant 8, 1821 mRNA. IRF3 NM 001571 Homo sapiens interferon regulatory factor 3 (IRF3), transcript variant 1, 1822 mRNA. IRF3 NR 045568 Homo sapiens interferon regulatory factor 3 (IRF3), transcript variant 9, 1823 non-coding RNA. IRF7 NM 001572 Homo sapiens interferon regulatory factor 7 (IRF7), transcript variant a, 1824 mRNA. IRF7 NM 004029 Homo sapiens interferon regulatory factor 7 (IRF7), transcript variant b, 1825 mRNA. IRF7 NM 004031 Homo sapiens interferon regulatory factor 7 (IRF7), transcript variant d, 1826 mRNA. IRF8 NM 002163 Homo sapiens interferon regulatory factor 8 (IRF8), mRNA. 1827 IRGM NM 001145805 Homo sapiens immunity related GTPase M (IRGM), mRNA. 1828 ISG15 NM 005101 Homo sapiens ISG15 ubiquitin-like modifier (ISG15), mRNA. 1829 ITK NM 005546 Homo sapiens IL2 inducible T-cell kinase (ITK), mRNA. 1830 ITSN2 NM 006277 Homo sapiens intersectin 2 (ITSN2), transcript variant 1, mRNA. 1831 ITSN2 NM 019595 Homo sapiens intersectin 2 (ITSN2), transcript variant 3, mRNA. 1832 ITSN2 NM 147152 Homo sapiens intersectin 2 (ITSN2), transcript variant 2, mRNA. 1833 JAGN1 NM 032492 Homo sapiens jagunal homolog 1 (Drosophila) (JAGNI), mRNA. 1834 JAK3 NM 000215 Homo sapiens Janus kinase 3 (JAK3), mRNA. 1835 JMY NM 152405 Homo sapiens junction mediating and regulatory protein, p53 cofactor 1836 (JMY), mRNA. JUN NM 002228 Homo sapiens Jun proto-oncogene, AP-1 transcription factor subunit 1837 (JUN), mRNA. KITLG NM 000899 Homo sapiens KIT ligand (KITLG), transcript variant b, mRNA. 1838 KITLG NM 003994 Homo sapiens KIT ligand (KITLG), transcript variant a, mRNA. 1839 LAMTOR2 NM 001145264 Homo sapiens late endosomal/lysosomal adaptor, MAPK and MTOR 1840 activator 2 (LAMTOR2), transcript variant 2, mRNA. LAMTOR2 NM 014017 Homo sapiens late endosomal/lysosomal adaptor, MAPK and MTOR 1841 activator 2 (LAMTOR2), transcript variant 1, mRNA. LCK NM 005356 Homo sapiens LCK proto-oncogene, Src family tyrosine kinase (LCK), 1842 transcript variant 2, mRNA. LCK NM 001042771 Homo sapiens LCK proto-oncogene, Src family tyrosine kinase (LCK), 1843 transcript variant 1, mRNA. LCP2 NM 005565 Homo sapiens lymphocyte cytosolic protein 2 (SH2 domain containing 1844 leukocyte protein of 76kDa) (LCP2), mRNA. LIG1 NM 000234 Homo sapiens DNA ligase 1 (LIG1), transcript variant 1, mRNA. 1845 LIG4 NM 001098268 Homo sapiens DNA ligase 4 (LIG4), transcript variant 3, mRNA. 1846 LIG4 NM 002312 Homo sapiens DNA ligase 4 (LIG4), transcript variant 1, mRNA. 1847 LIG4 NM 206937 Homo sapiens DNA ligase 4 (LIG4), transcript variant 2, mRNA. 1848 LRBA NM 001199282 Homo sapiens LPS responsive beige-like anchor protein (LRBA), 1849 transcript variant 1, mRNA. LRBA NM 006726 Homo sapiens LPS responsive beige-like anchor protein (LRBA), 1850 transcript variant 2, mRNA. LYST NM 000081 Homo sapiens lysosomal trafficking regulator (LYST), transcript variant 1851 1, mRNA. MAGEA9 NM 005365 Homo sapiens MAGE family member A9 (MAGEA9), mRNA. 1852 MAGEA9B NM 001080790 Homo sapiens MAGE family member A9B (MAGEA9B), mRNA. 1853 MAGT1 NM 032121 Homo sapiens magnesium transporter 1 (MAGT1), mRNA. 1854 MALT1 NM 006785 Homo sapiens MALT1 paracaspase (MALT1), transcript variant 1, 1855 mRNA. MALT1 NM 173844 Homo sapiens MALT1 paracaspase (MALT1), transcript variant 2, 1856 mRNA. MAP3K2 NM 006609 Homo sapiens mitogen-activated protein kinase kinase kinase 2 1857 (MAP3K2), mRNA. MAPK1 NM 002745 Homo sapiens mitogen-activated protein kinase 1 (MAPK1), transcript 1858 variant 1, mRNA. MAPK1 NM 138957 Homo sapiens mitogen-activated protein kinase 1 (MAPK1), transcript 1859 variant 2, mRNA. MAPK3 NM 001040056 Homo sapiens mitogen-activated protein kinase 3 (MAPK3), transcript 1860 variant 2, mRNA. MAPK3 NM 001109891 Homo sapiens mitogen-activated protein kinase 3 (MAPK3), transcript 1861 variant 3, mRNA. MAPK3 NM 002746 Homo sapiens mitogen-activated protein kinase 3 (MAPK3), transcript 1862 variant 1, mRNA. MAVS NM 020746 Homo sapiens mitochondrial antiviral signaling protein (MAVS), 1863 transcript variant 1, mRNA. MAVS NM 001206491 Homo sapiens mitochondrial antiviral signaling protein (MAVS), 1864 transcript variant 3, mRNA. MAVS NR 037921 Homo sapiens mitochondrial antiviral signaling protein (MAVS), 1865 transcript variant 2, non-coding RNA. MECP2 NM 004992 Homo sapiens methyl-CpG binding protein 2 (MECP2), transcript 1866 variant 1, mRNA. MECP2 NM 001110792 Homo sapiens methyl-CpG binding protein 2 (MECP2), transcript 1867 variant 2, mRNA. MEX3C NM 016626 Homo sapiens mex-3 RNA binding family member C (MEX3C), 1868 mRNA. MRE11A NM 005590 Homo sapiens MRE11 homolog A, double strand break repair nuclease 1869 (MRE11A), transcript variant 2, mRNA. MRE11A NM 005591 Homo sapiens MRE11 homolog A, double strand break repair nuclease 1870 (MRE11A), transcript variant 1, mRNA. MS4A1 NM 021950 Homo sapiens membrane spanning 4-domains A1 (MS4A1), transcript 1871 variant 3, mRNA. MS4A1 NM 152866 Homo sapiens membrane spanning 4-domains A1 (MS4A1), transcript 1872 variant 1, mRNA. MSN NM 002444 Homo sapiens moesin (MSN), mRNA. 1873 MYD88 NM 001172566 Homo sapiens myeloid differentiation primary response 88 (MYD88), 1874 transcript variant 5, mRNA. MYD88 NM 001172567 Homo sapiens myeloid differentiation primary response 88 (MYD88), 1875 transcript variant 1, mRNA. MYD88 NM 001172568 Homo sapiens myeloid differentiation primary response 88 (MYD88), 1876 transcript variant 3, mRNA. MYD88 NM 001172569 Homo sapiens myeloid differentiation primary response 88 (MYD88), 1877 transcript variant 4, mRNA. MYD88 NM 002468 Homo sapiens myeloid differentiation primary response 88 (MYD88), 1878 transcript variant 2, mRNA. NBN NM 002485 Homo sapiens nibrin (NBN), mRNA. 1879 NFIC NM 001245005 Homo sapiens nuclear factor I C (NFIC), transcript variant 4, mRNA. 1880 NFIC NM 205843 Homo sapiens nuclear factor I C (NFIC), transcript variant 2, mRNA. 1881 NFIC NM 001245002 Homo sapiens nuclear factor I C (NFIC), transcript variant 1, mRNA. 1882 NFIC NM 001245004 Homo sapiens nuclear factor I C (NFIC), transcript variant 3, mRNA. 1883 NFIC NM 005597 Homo sapiens nuclear factor I C (NFIC), transcript variant 5, mRNA. 1884 NFKB1 NM 003998 Homo sapiens nuclear factor of kappa light polypeptide gene enhancer 1885 in B-cells 1 (NFKB1), transcript variant 1, mRNA. NFKB1 NM 001165412 Homo sapiens nuclear factor of kappa light polypeptide gene enhancer 1886 in B-cells 1 (NFKB1), transcript variant 2, mRNA. NFKB2 NM 001077494 Homo sapiens nuclear factor of kappa light polypeptide gene enhancer 1887 in B-cells 2 (NFKB2), transcript variant 1, mRNA. NFKB2 NM 002502 Homo sapiens nuclear factor of kappa light polypeptide gene enhancer 1888 in B-cells 2 (NFKB2), transcript variant 2, mRNA. NFKB2 NM 001261403 Homo sapiens nuclear factor of kappa light polypeptide gene enhancer 1889 in B-cells 2 (NFKB2), transcript variant 4, mRNA. NFKBIA NM 020529 Homo sapiens NFKB inhibitor alpha (NFKBIA), mRNA. 1890 NHEJ1 NM 024782 Homo sapiens non-homologous end joining factor 1 (NHEJ1), mRNA. 1891 NLRP3 NM 183395 Homo sapiens NLR family, pyrin domain containing 3 (NLRP3), 1892 transcript variant 2, mRNA. NLRP3 NM 004895 Homo sapiens NLR family, pyrin domain containing 3 (NLRP3), 1893 transcript variant 1, mRNA. NLRP3 NM 001127462 Homo sapiens NLR family, pyrin domain containing 3 (NLRP3), 1894 transcript variant 5, mRNA. NLRP3 NM 001127461 Homo sapiens NLR family, pyrin domain containing 3 (NLRP3), 1895 transcript variant 4, mRNA. NLRP3 NM 001079821 Homo sapiens NLR family, pyrin domain containing 3 (NLRP3), 1896 transcript variant 3, mRNA. NLRP3 NM 001243133 Homo sapiens NLR family, pyrin domain containing 3 (NLRP3), 1897 transcript variant 6, mRNA. NOD2 NM 022162 Homo sapiens nucleotide-binding oligomerization domain containing 2 1898 (NOD2), mRNA. ORAI1 NM 032790 Homo sapiens ORAI calcium release-activated calcium modulator 1 1899 (ORAI1), mRNA. OSTM1 NM 014028 Homo sapiens osteopetrosis associated transmembrane protein 1 1900 (OSTM1), mRNA. PGM3 NM 001199917 Homo sapiens phosphoglucomutase 3 (PGM3), transcript variant 1, 1901 mRNA. PGM3 NM 001199918 Homo sapiens phosphoglucomutase 3 (PGM3), transcript variant 3, 1902 mRNA. PGM3 NM 015599 Homo sapiens phosphoglucomutase 3 (PGM3), transcript variant 2, 1903 mRNA. PGM3 NM 001199919 Homo sapiens phosphoglucomutase 3 (PGM3), transcript variant 4, 1904 mRNA. PIAS1 NM 016166 Homo sapiens protein inhibitor of activated STAT 1 (PIAS1), transcript 1905 variant 2, mRNA. PIK3R1 NM 181523 Homo sapiens phosphoinositide-3-kinase regulatory subunit 1 1906 (PIK3R1), transcript variant 1, mRNA. PIK3R1 NM 181524 Homo sapiens phosphoinositide-3-kinase regulatory subunit 1 1907 (PIK3R1), transcript variant 3, mRNA. PIK3R1 NM 181504 Homo sapiens phosphoinositide-3-kinase regulatory subunit 1 1908 (PIK3R1), transcript variant 2, mRNA. PIK3R1 NM 001242466 Homo sapiens phosphoinositide-3-kinase regulatory subunit 1 1909 (PIK3R1), transcript variant 4, mRNA. PLCG2 NM 002661 Homo sapiens phospholipase C gamma 2 (PLCG2), mRNA. 1910 PMS2 NM 000535 Homo sapiens PMS1 homolog 2, mismatch repair system component 1911 (PMS2), transcript variant 1, mRNA. PNP NM 000270 Homo sapiens purine nucleoside phosphorylase (PNP), mRNA. 1912 POLA1 NM 016937 Homo sapiens polymerase (DNA directed), alpha 1, catalytic subunit 1913 (POLA1), mRNA. POLE NM 006231 Homo sapiens DNA polymerase epsilon, catalytic subunit (POLE), 1914 mRNA. PRF1 NM 001083116 Homo sapiens perforin 1 (PRF1), transcript variant 2, mRNA. 1915 PRF1 NM 005041 Homo sapiens perforin 1 (PRF1), transcript variant 1, mRNA. 1916 PRKCD NM 006254 Homo sapiens protein kinase C delta (PRKCD), transcript variant 1, 1917 mRNA. PRKCD NM 212539 Homo sapiens protein kinase C delta (PRKCD), transcript variant 2, 1918 mRNA. PRKDC NM 001081640 Homo sapiens protein kinase, DNA-activated, catalytic polypeptide 1919 (PRKDC), transcript variant 2, mRNA. PRKDC NM 006904 Homo sapiens protein kinase, DNA-activated, catalytic polypeptide 1920 (PRKDC), transcript variant 1, mRNA. PROC NM 000312 Homo sapiens protein C, inactivator of coagulation factors Va and VIIIa 1921 (PROC), mRNA. PSMB8 NM 004159 Homo sapiens proteasome (prosome, macropain) subunit, beta type, 8 1922 (PSMB8), transcript variant 1, mRNA. PSMB8 NM 148919 Homo sapiens proteasome (prosome, macropain) subunit, beta type, 8 1923 (PSMB8), transcript variant 2, mRNA. PTEN NM 000314 Homo sapiens phosphatase and tensin homolog (PTEN), transcript 1924 variant 1, mRNA. PTPRC NM 001267798 Homo sapiens protein tyrosine phosphatase, receptor type C (PTPRC), 1925 transcript variant 5, mRNA. PTPRC NM 002838 Homo sapiens protein tyrosine phosphatase, receptor type C (PTPRC), 1926 transcript variant 1, mRNA. PTPRC NM 080921 Homo sapiens protein tyrosine phosphatase, receptor type C (PTPRC), 1927 transcript variant 2, mRNA. PTPRC NR 052021 Homo sapiens protein tyrosine phosphatase, receptor type C (PTPRC), 1928 transcript variant 4, non-coding RNA. PURA NM 005859 Homo sapiens purine rich element binding protein A (PURA), mRNA. 1929 RAB27A NM 183235 Homo sapiens RAB27A, member RAS oncogene family (RAB27A), 1930 transcript variant 3, mRNA. RAB27A NM 183236 Homo sapiens RAB27A, member RAS oncogene family (RAB27A), 1931 transcript variant 4, mRNA. RAB27A NM 004580 Homo sapiens RAB27A, member RAS oncogene family (RAB27A), 1932 transcript variant 1, mRNA. RAB27A NM 183234 Homo sapiens RAB27A, member RAS oncogene family (RAB27A), 1933 transcript variant 2, mRNA. RAB7A NM 004637 Homo sapiens RAB7A, member RAS oncogene family (RAB7A), 1934 mRNA. RABGEF1 NM 014504 Homo sapiens RAB guanine nucleotide exchange factor (GEF) 1 1935 (RABGEF1), transcript variant 4, mRNA. RAC2 NM 002872 Homo sapiens ras-related C3 botulinum toxin substrate 2 (rho family, 1936 small GTP binding protein Rac2) (RAC2), mRNA. RAD51 NM 001164270 Homo sapiens RAD51 recombinase (RAD51), transcript variant 3, 1937 mRNA. RAD51 NM 002875 Homo sapiens RAD51 recombinase (RAD51), transcript variant 1, 1938 mRNA. RAD51 NM 133487 Homo sapiens RAD51 recombinase (RAD51), transcript variant 2, 1939 mRNA. RAD51 NM 001164269 Homo sapiens RAD51 recombinase (RAD51), transcript variant 4, 1940 mRNA. RAG1 NM 000448 Homo sapiens recombination activating gene 1 (RAG1), mRNA. 1941 RAG2 NM 000536 Homo sapiens recombination activating gene 2 (RAG2), transcript 1942 variant 1, mRNA. RAG2 NM 001243785 Homo sapiens recombination activating gene 2 (RAG2), transcript 1943 variant 3, mRNA. RAG2 NM 001243786 Homo sapiens recombination activating gene 2 (RAG2), transcript 1944 variant 4, mRNA. RBCK1 NM 006462 Homo sapiens RANBP2-type and C3HC4-type zinc finger containing 1 1945 (RBCK1), transcript variant 1, mRNA. RBCK1 NM 031229 Homo sapiens RANBP2-type and C3HC4-type zinc finger containing 1 1946 (RBCK1), transcript variant 2, mRNA. RFX5 NM 000449 Homo sapiens regulatory factor X5 (RFX5), transcript variant 1, 1947 mRNA. RFX5 NM 001025603 Homo sapiens regulatory factor X5 (RFX5), transcript variant 2, 1948 mRNA. RFXANK NM 003721 Homo sapiens regulatory factor X associated ankyrin containing protein 1949 (RFXANK), transcript variant 1, mRNA. RFXANK NM 134440 Homo sapiens regulatory factor X associated ankyrin containing protein 1950 (RFXANK), transcript variant 2, mRNA. RFXAP NM 000538 Homo sapiens regulatory factor X associated protein (RFXAP), mRNA. 1951 RIPK1 NM 003804 Homo sapiens receptor (TNFRSF)-interacting serine-threonine kinase 1 1952 (RIPK1), mRNA. RIPK3 NM 006871 Homo sapiens receptor-interacting serine-threonine kinase 3 (RIPK3), 1953 mRNA. RMRP NR 003051 Homo sapiens RNA component of mitochondrial RNA processing 1954 endoribonuclease (RMRP), RNase MRP RNA. RNASEH2A NM 006397 Homo sapiens ribonuclease H2, subunit A (RNASEH2A), mRNA. 1955 RNASEH2B NM 001142279 Homo sapiens ribonuclease H2, subunit B (RNASEH2B), transcript 1956 variant 2, mRNA. RNASEH2B NM 024570 Homo sapiens ribonuclease H2, subunit B (RNASEH2B), transcript 1957 variant 1, mRNA. RNASEH2C NM 032193 Homo sapiens ribonuclease H2, subunit C (RNASEH2C), mRNA. 1958 RNASEL NM 021133 Homo sapiens ribonuclease L (2′,5′-oligoisoadenylate synthetase- 1959 dependent) (RNASEL), mRNA. RNF168 NM 152617 Homo sapiens ring finger protein 168 (RNF168), mRNA. 1960 RNF31 NM 017999 Homo sapiens ring finger protein 31 (RNF31), mRNA. 1961 RNU4ATAC NR 023343 Homo sapiens RNA, U4atac small nuclear (U12-dependent splicing) 1962 (RNU4ATAC), small nuclear RNA. RTEL1 NM 016434 Homo sapiens regulator of telomere elongation helicase 1 (RTEL1), 1963 transcript variant 1, mRNA. RTEL1 NM 032957 Homo sapiens regulator of telomere elongation helicase 1 (RTEL1), 1964 transcript variant 2, mRNA. RTEL1- NR 037882 Homo sapiens RTEL1-TNFRSF6B readthrough (NMD candidate) 1965 TNFRSF6B (RTEL1-TNFRSF6B), long non-coding RNA. SALL2 NM 005407 Homo sapiens spalt like transcription factor 2 (SALL2), transcript 1966 variant 1, mRNA. SAMHD1 NM 015474 Homo sapiens SAM domain and HD domain 1 (SAMHD1), mRNA. 1967 SBDS NM 016038 Homo sapiens Shwachman-Bodian-Diamond syndrome (SBDS), 1968 mRNA. SH2D1A NM 001114937 Homo sapiens SH2 domain containing 1A (SH2D1A), transcript variant 1969 2, mRNA. SH2D1A NM 002351 Homo sapiens SH2 domain containing 1A (SH2D1A), transcript variant 1970 1, mRNA. SHARPIN NM 030974 Homo sapiens SHANK-associated RH domain interactor (SHARPIN), 1971 transcript variant 1, mRNA. SHARPIN NR 038270 Homo sapiens SHANK-associated RH domain interactor (SHARPIN), 1972 transcript variant 2, non-coding RNA. SKIV2L NM 006929 Homo sapiens superkiller viralicidic activity 2-like (S. cerevisiae) 1973 (SKIV2L), mRNA. SLC37A4 NM 001164277 Homo sapiens solute carrier family 37 (glucose-6-phosphate 1974 transporter), member 4 (SLC37A4), transcript variant 1, mRNA. SLC37A4 NM 001164278 Homo sapiens solute carrier family 37 (glucose-6-phosphate 1975 transporter), member 4 (SLC37A4), transcript variant 2, mRNA. SLC37A4 NM 001164279 Homo sapiens solute carrier family 37 (glucose-6-phosphate 1976 transporter), member 4 (SLC37A4), transcript variant 3, mRNA. SLC37A4 NM 001467 Homo sapiens solute carrier family 37 (glucose-6-phosphate 1977 transporter), member 4 (SLC37A4), transcript variant 4, mRNA. SLC37A4 NM 001164280 Homo sapiens solute carrier family 37 (glucose-6-phosphate 1978 transporter), member 4 (SLC37A4), transcript variant 5, mRNA. SLC46A1 NM 001242366 Homo sapiens solute carrier family 46 member 1 (SLC46A1), transcript 1979 variant 2, mRNA. SLC46A1 NM 080669 Homo sapiens solute carrier family 46 member 1 (SLC46A1), transcript 1980 variant 1, mRNA. SLC8A1 NM 001112800 Homo sapiens solute carrier family 8 member A1 (SLC8A1), transcript 1981 variant B, mRNA. SLC8A1 NM 001112801 Homo sapiens solute carrier family 8 member A1 (SLC8A1), transcript 1982 variant C, mRNA. SLC8A1 NM 001112802 Homo sapiens solute carrier family 8 member A1 (SLC8A1), transcript 1983 variant D, mRNA. SLC8A1 NM 001252624 Homo sapiens solute carrier family 8 member A1 (SLC8A1), transcript 1984 variant E, mRNA. SLC8A1 NM 021097 Homo sapiens solute carrier family 8 member A1 (SLC8A1), transcript 1985 variant A, mRNA. SMAD2 NM 001003652 Homo sapiens SMAD family member 2 (SMAD2), transcript variant 2, 1986 mRNA. SMAD2 NM 001135937 Homo sapiens SMAD family member 2 (SMAD2), transcript variant 3, 1987 mRNA. SMAD2 NM 005901 Homo sapiens SMAD family member 2 (SMAD2), transcript variant 1, 1988 mRNA. SMAD3 NM 005902 Homo sapiens SMAD family member 3 (SMAD3), transcript variant 1, 1989 mRNA. SMAD3 NM 001145102 Homo sapiens SMAD family member 3 (SMAD3), transcript variant 2, 1990 mRNA. SMAD3 NM 001145103 Homo sapiens SMAD family member 3 (SMAD3), transcript variant 3, 1991 mRNA. SMAD3 NM 001145104 Homo sapiens SMAD family member 3 (SMAD3), transcript variant 4, 1992 mRNA. SMAD4 NM 005359 Homo sapiens SMAD family member 4 (SMAD4), mRNA. 1993 SNAP29 NM 004782 Homo sapiens synaptosomal-associated protein, 29 kDa (SNAP29), 1994 mRNA. SNAR-A1 NR 004435 Homo sapiens small ILF3/NF90-associated RNA A1 (SNAR-A1), small 1995 nuclear RNA. SNAR-A10 NR 024229 Homo sapiens small ILF3/NF90-associated RNA A10 (SNAR-A10), 1996 small nuclear RNA. SNAR-A11 NR 024225 Homo sapiens small ILF3/NF90-associated RNA A11 (SNAR-A11), 1997 small nuclear RNA. SNAR-A12 NR 004437 Homo sapiens small ILF3/NF90-associated RNA A12 (SNAR-A12), 1998 small nuclear RNA. SNAR-A13 NR 024216 Homo sapiens small ILF3/NF90-associated RNA A13 (SNAR-A13), 1999 small nuclear RNA. SNAR-A14 NR 024242 Homo sapiens small ILF3/NF90-associated RNA A14 (SNAR-A14), 2000 small nuclear RNA. SNAR-A2 NR 004436 Homo sapiens small ILF3/NF90-associated RNA A2 (SNAR-A2), small 2001 nuclear RNA. SNAR-A3 NR 024214 Homo sapiens small ILF3/NF90-associated RNA A3 (SNAR-A3), small 2002 nuclear RNA. SNAR-A4 NR 024215 Homo sapiens small ILF3/NF90-associated RNA A4 (SNAR-A4), small 2003 nuclear RNA. SNAR-A5 NR 024223 Homo sapiens small ILF3/NF90-associated RNA A5 (SNAR-A5), small 2004 nuclear RNA. SNAR-A6 NR 024227 Homo sapiens small ILF3/NF90-associated RNA A6 (SNAR-A6), small 2005 nuclear RNA. SNAR-A7 NR 024224 Homo sapiens small ILF3/NF90-associated RNA A7 (SNAR-A7), small 2006 nuclear RNA. SNAR-A8 NR 024228 Homo sapiens small ILF3/NF90-associated RNA A8 (SNAR-A8), small 2007 nuclear RNA. SNAR-A9 NR 024226 Homo sapiens small ILF3/NF90-associated RNA A9 (SNAR-A9), small 2008 nuclear RNA. SNAR-B1 NR 024231 Homo sapiens small ILF3/NF90-associated RNA B1 (SNAR-B1), small 2009 nuclear RNA. SNAR-B2 NR 024230 Homo sapiens small ILF3/NF90-associated RNA B2 (SNAR-B2), small 2010 nuclear RNA. SNAR-C1 NR 024220 Homo sapiens small ILF3/NF90-associated RNA C1 (SNAR-C1), small 2011 nuclear RNA. SNAR-C2 NR 024217 Homo sapiens small ILF3/NF90-associated RNA C2 (SNAR-C2), small 2012 nuclear RNA. SNAR-C3 NR 024221 Homo sapiens small ILF3/NF90-associated RNA C3 (SNAR-C3), small 2013 nuclear RNA. SNAR-C4 NR 024218 Homo sapiens small ILF3/NF90-associated RNA C4 (SNAR-C4), small 2014 nuclear RNA. SNAR-C5 NR 024219 Homo sapiens small ILF3/NF90-associated RNA C5 (SNAR-C5), small 2015 nuclear RNA. SNAR-D NR 024243 Homo sapiens small ILF3/NF90-associated RNA D (SNAR-D), small 2016 nuclear RNA. SNAR-E NR 024258 Homo sapiens small ILF3/NF90-associated RNA E (SNAR-E), small 2017 nuclear RNA. SNAR-F NR 004384 Homo sapiens small ILF3/NF90-associated RNA F (SNAR-F), small 2018 nuclear RNA. SNAR-G1 NR 004383 Homo sapiens small ILF3/NF90-associated RNA G1 (SNAR-G1), small 2019 nuclear RNA. SNAR-G2 NR 024244 Homo sapiens small ILF3/NF90-associated RNA G2 (SNAR-G2), small 2020 nuclear RNA. SNAR-H NR 024342 Homo sapiens small ILF3/NF90-associated RNA H (SNAR-H), small 2021 nuclear RNA. SNAR-I NR 024343 Homo sapiens small ILF3/NF90-associated RNA I (SNAR-I), small 2022 nuclear RNA. SNCA NM 000345 Homo sapiens synuclein, alpha (non A4 component of amyloid 2023 precursor) (SNCA), transcript variant 1, mRNA. SNCA NM 001146054 Homo sapiens synuclein, alpha (non A4 component of amyloid 2024 precursor) (SNCA), transcript variant 2, mRNA. SNCA NM 001146055 Homo sapiens synuclein, alpha (non A4 component of amyloid 2025 precursor) (SNCA), transcript variant 3, mRNA. SNCA NM 007308 Homo sapiens synuclein, alpha (non A4 component of amyloid 2026 precursor) (SNCA), transcript variant 4, mRNA. SNX10 NM 013322 Homo sapiens sorting nexin 10 (SNX10), transcript variant 2, mRNA. 2027 SNX10 NM 001199835 Homo sapiens sorting nexin 10 (SNX10), transcript variant 1, mRNA. 2028 SNX10 NM 001199837 Homo sapiens sorting nexin 10 (SNX10), transcript variant 3, mRNA. 2029 SNX10 NM 001199838 Homo sapiens sorting nexin 10 (SNX10), transcript variant 4, mRNA. 2030 SNX10 NR 037670 Homo sapiens sorting nexin 10 (SNX10), transcript variant 5, non- 2031 coding RNA. SP110 NM 004509 Homo sapiens SP110 nuclear body protein (SP110), transcript variant a, 2032 mRNA. SP110 NM 080424 Homo sapiens SP 110 nuclear body protein (SP110), transcript variant c, 2033 mRNA. SP110 NM 001185015 Homo sapiens SP 110 nuclear body protein (SP110), transcript variant d, 2034 mRNA. SP110 NM 004510 Homo sapiens SP 110 nuclear body protein (SP110), transcript variant b, 2035 mRNA. SP140 NM 001005176 Homo sapiens SP140 nuclear body protein (SP140), transcript variant 2, 2036 mRNA. SP140 NM 007237 Homo sapiens SP140 nuclear body protein (SP140), transcript variant 1, 2037 mRNA. SPINK5 NM 001127698 Homo sapiens serine peptidase inhibitor, Kazal type 5 (SPINK5), 2038 transcript variant 1, mRNA. SPINK5 NM 006846 Homo sapiens serine peptidase inhibitor, Kazal type 5 (SPINK5), 2039 transcript variant 2, mRNA. SPINK5 NM 001127699 Homo sapiens serine peptidase inhibitor, Kazal type 5 (SPINK5), 2040 transcript variant 3, mRNA. SQSTM1 NM 003900 Homo sapiens sequestosome 1 (SQSTM1), transcript variant 1, mRNA. 2041 SQSTM1 NM 001142298 Homo sapiens sequestosome 1 (SQSTM1), transcript variant 2, mRNA. 2042 SQSTM1 NM 001142299 Homo sapiens sequestosome 1 (SQSTM1), transcript variant 3, mRNA. 2043 SRSF1 NM 001078166 Homo sapiens serine and arginine rich splicing factor 1 (SRSF1), 2044 transcript variant 2, mRNA. SRSF1 NM 006924 Homo sapiens serine and arginine rich splicing factor 1 (SRSF1), 2045 transcript variant 1, mRNA. SRSF1 NR 034041 Homo sapiens serine and arginine rich splicing factor 1 (SRSF1), 2046 transcript variant 3, non-coding RNA. STAT1 NM 007315 Homo sapiens signal transducer and activator of transcription 1 2047 (STAT1), transcript variant alpha, mRNA. STAT1 NM 139266 Homo sapiens signal transducer and activator of transcription 1 2048 (STAT1), transcript variant beta, mRNA. STAT2 NM 005419 Homo sapiens signal transducer and activator of transcription 2, 113 kDa 2049 (STAT2), transcript variant 1, mRNA. STAT2 NM 198332 Homo sapiens signal transducer and activator of transcription 2, 113 kDa 2050 (STAT2), transcript variant 2, mRNA. STAT3 NM 003150 Homo sapiens signal transducer and activator of transcription 3 2051 (STAT3), transcript variant 2, mRNA. STAT3 NM 139276 Homo sapiens signal transducer and activator of transcription 3 2052 (STAT3), transcript variant 1, mRNA. STAT3 NM 213662 Homo sapiens signal transducer and activator of transcription 3 2053 (STAT3), transcript variant 3, mRNA. STAT5B NM 012448 Homo sapiens signal transducer and activator of transcription 5B 2054 (STAT5B), mRNA. STIM1 NM 003156 Homo sapiens stromal interaction molecule 1 (STIM1), transcript 2055 variant 2, mRNA. STK4 NM 006282 Homo sapiens serine/threonine kinase 4 (STK4), mRNA. 2056 STX11 NM 003764 Homo sapiens syntaxin 11 (STX11), mRNA. 2057 STXBP2 NM 001127396 Homo sapiens syntaxin binding protein 2 (STXBP2), transcript variant 2058 2, mRNA. STXBP2 NM 001272034 Homo sapiens syntaxin binding protein 2 (STXBP2), transcript variant 2059 3, mRNA. STXBP2 NM 006949 Homo sapiens syntaxin binding protein 2 (STXBP2), transcript variant 2060 1, mRNA. STXBP2 NR 073560 Homo sapiens syntaxin binding protein 2 (STXBP2), transcript variant 2061 4, non-coding RNA. SYNCRIP NM 001159673 Homo sapiens synaptotagmin binding cytoplasmic RNA interacting 2062 protein (SYNCRIP), transcript variant 2, mRNA. SYNCRIP NM 001159674 Homo sapiens synaptotagmin binding cytoplasmic RNA interacting 2063 protein (SYNCRIP), transcript variant 3, mRNA. SYNCRIP NM 001159676 Homo sapiens synaptotagmin binding cytoplasmic RNA interacting 2064 protein (SYNCRIP), transcript variant 5, mRNA. SYNCRIP NM 001159677 Homo sapiens synaptotagmin binding cytoplasmic RNA interacting 2065 protein (SYNCRIP), transcript variant 6, mRNA. SYNCRIP NM 001253771 Homo sapiens synaptotagmin binding cytoplasmic RNA interacting 2066 protein (SYNCRIP), transcript variant 7, mRNA. SYNCRIP NM 001159675 Homo sapiens synaptotagmin binding cytoplasmic RNA interacting 2067 protein (SYNCRIP), transcript variant 4, mRNA. SYNCRIP NM 006372 Homo sapiens synaptotagmin binding cytoplasmic RNA interacting 2068 protein (SYNCRIP), transcript variant 1, mRNA. T NM 001270484 Homo sapiens T brachyury transcription factor (T), transcript variant 2, 2069 mRNA. T NM 003181 Homo sapiens T brachyury transcription factor (T), transcript variant 1, 2070 mRNA. TAP1 NM 000593 Homo sapiens transporter 1, ATP binding cassette subfamily B member 2071 (TAP1), transcript variant 1, mRNA. TAP2 NM 018833 Homo sapiens transporter 2, ATP binding cassette subfamily B member 2072 (TAP2), transcript variant 2, mRNA. TAP2 NM 000544 Homo sapiens transporter 2, ATP binding cassette subfamily B member 2073 (TAP2), transcript variant 1, B allele, mRNA. TAPBP NM 003190 Homo sapiens TAP binding protein (tapasin) (TAPBP), transcript 2074 variant 1, mRNA. TAPBP NM 172209 Homo sapiens TAP binding protein (tapasin) (TAPBP), transcript 2075 variant 3, mRNA. TAPBP NM 172208 Homo sapiens TAP binding protein (tapasin) (TAPBP), transcript 2076 variant 2, mRNA. TAZ NM 000116 Homo sapiens tafazzin (TAZ), transcript variant 1, mRNA. 2077 TAZ NM 181312 Homo sapiens tafazzin (TAZ), transcript variant 3, mRNA. 2078 TAZ NM 181311 Homo sapiens tafazzin (TAZ), transcript variant 2, mRNA. 2079 TAZ NM 181313 Homo sapiens tafazzin (TAZ), transcript variant 4, mRNA. 2080 TAZ NR 024048 Homo sapiens tafazzin (TAZ), transcript variant 5, non-coding RNA. 2081 TBK1 NM 013254 Homo sapiens TANK binding kinase 1 (TBK1), mRNA. 2082 TBX1 NM 005992 Homo sapiens T-box 1 (TBX1), transcript variant B, mRNA. 2083 TBX1 NM 080646 Homo sapiens T-box 1 (TBX1), transcript variant A, mRNA. 2084 TBX1 NM 080647 Homo sapiens T-box 1 (TBX1), transcript variant C, mRNA. 2085 TCIRG1 NM 006019 Homo sapiens T-cell immune regulator 1, ATPase H+ transporting V0 2086 subunit a3 (TCIRG1), transcript variant 1, mRNA. TCIRG1 NM 006053 Homo sapiens T-cell immune regulator 1, ATPase H+ transporting V0 2087 subunit a3 (TCIRG1), transcript variant 2, mRNA. TICAM1 NM 182919 Homo sapiens toll like receptor adaptor molecule 1 (TICAM1), mRNA. 2088 TLR3 NM 003265 Homo sapiens toll like receptor 3 (TLR3), mRNA. 2089 TLR4 NM 003266 Homo sapiens toll like receptor 4 (TLR4), transcript variant 3, mRNA. 2090 TLR4 NM 138554 Homo sapiens toll like receptor 4 (TLR4), transcript variant 1, mRNA. 2091 TLR4 NM 138557 Homo sapiens toll like receptor 4 (TLR4), transcript variant 4, mRNA. 2092 TMEM173 NM 198282 Homo sapiens transmembrane protein 173 (TMEM173), mRNA. 2093 TNF NM 000594 Homo sapiens tumor necrosis factor (TNF), mRNA. 2094 TNFAIP3 NM 001270507 Homo sapiens TNF alpha induced protein 3 (TNFAIP3), transcript 2095 variant 2, mRNA. TNFAIP3 NM 001270508 Homo sapiens TNF alpha induced protein 3 (TNFAIP3), transcript 2096 variant 1, mRNA. TNFAIP3 NM 006290 Homo sapiens TNF alpha induced protein 3 (TNFAIP3), transcript 2097 variant 3, mRNA. TNFRSF11A NM 003839 Homo sapiens tumor necrosis factor receptor superfamily, member 11a, 2098 NFKB activator (TNFRSF11A), transcript variant 1, mRNA. TNFRSF11A NM 001270949 Homo sapiens tumor necrosis factor receptor superfamily, member 11a, 2099 NFKB activator (TNFRSF11A), transcript variant 2, mRNA. TNFRSF11A NM 001270950 Homo sapiens tumor necrosis factor receptor superfamily, member 11a, 2100 NFKB activator (TNFRSF11A), transcript variant 3, mRNA. TNFRSF11A NM 001270951 Homo sapiens tumor necrosis factor receptor superfamily, member 11a, 2101 NFKB activator (TNFRSF11A), transcript variant 4, mRNA. TNFRSF11B NM 002546 Homo sapiens tumor necrosis factor receptor superfamily, member 1 lb 2102 (TNFRSF11B), mRNA. TNFRSF13B NM 012452 Homo sapiens TNF receptor superfamily member 13B (TNFRSF13B), 2103 mRNA. TNFRSF4 NM 003327 Homo sapiens TNF receptor superfamily member 4 (TNFRSF4), 2104 mRNA. TNFRSF8 NM 001243 Homo sapiens TNF receptor superfamily member 8 (TNFRSF8), 2105 transcript variant 1, mRNA. TNFSF11 NM 003701 Homo sapiens tumor necrosis factor (ligand) superfamily, member 11 2106 (TNFSF11), transcript variant 1, mRNA. TNFSF11 NM 033012 Homo sapiens tumor necrosis factor (ligand) superfamily, member 11 2107 (TNFSF11), transcript variant 2, mRNA. TNFSF12 NM 003809 Homo sapiens tumor necrosis factor superfamily member 12 2108 (TNFSF12), transcript variant 1, mRNA. TNFSF12 NR 037146 Homo sapiens tumor necrosis factor superfamily member 12 2109 (TNFSF12), transcript variant 2, non-coding RNA. TP53 NM 000546 Homo sapiens tumor protein p53 (TP53), transcript variant 1, mRNA. 2110 TP53 NM 001126112 Homo sapiens tumor protein p53 (TP53), transcript variant 2, mRNA. 2111 TP53 NM 001126113 Homo sapiens tumor protein p53 (TP53), transcript variant 4, mRNA. 2112 TP53 NM 001126114 Homo sapiens tumor protein p53 (TP53), transcript variant 3, mRNA. 2113 TP53 NM 001126115 Homo sapiens tumor protein p53 (TP53), transcript variant 5, mRNA. 2114 TP53 NM 001126116 Homo sapiens tumor protein p53 (TP53), transcript variant 6, mRNA. 2115 TP53 NM 001126117 Homo sapiens tumor protein p53 (TP53), transcript variant 7, mRNA. 2116 TP53 NM 001126118 Homo sapiens tumor protein p53 (TP53), transcript variant 8, mRNA. 2117 TP53 NM 001276695 Homo sapiens tumor protein p53 (TP53), transcript variant 4, mRNA. 2118 TP53 NM 001276696 Homo sapiens tumor protein p53 (TP53), transcript variant 3, mRNA. 2119 TP53 NM 001276697 Homo sapiens tumor protein p53 (TP53), transcript variant 5, mRNA. 2120 TP53 NM 001276698 Homo sapiens tumor protein p53 (TP53), transcript variant 6, mRNA. 2121 TP53 NM 001276699 Homo sapiens tumor protein p53 (TP53), transcript variant 7, mRNA. 2122 TP53 NM 001276760 Homo sapiens tumor protein p53 (TP53), transcript variant 1, mRNA. 2123 TP53 NM 001276761 Homo sapiens tumor protein p53 (TP53), transcript variant 2, mRNA. 2124 TRAF3 NM 001199427 Homo sapiens TNF receptor associated factor 3 (TRAF3), transcript 2125 variant 4, mRNA. TRAF3 NM 003300 Homo sapiens TNF receptor associated factor 3 (TRAF3), transcript 2126 variant 3, mRNA. TRAF3 NM 145725 Homo sapiens TNF receptor associated factor 3 (TRAF3), transcript 2127 variant 1, mRNA. TRAF3 NM 145726 Homo sapiens TNF receptor associated factor 3 (TRAF3), transcript 2128 variant 2, mRNA. TRAF6 NM 004620 Homo sapiens TNF receptor-associated factor 6, E3 ubiquitin protein 2129 ligase (TRAF6), transcript variant 2, mRNA. TRAF6 NM 145803 Homo sapiens TNF receptor-associated factor 6, E3 ubiquitin protein 2130 ligase (TRAF6), transcript variant 1, mRNA. TREX1 NM 007248 Homo sapiens three prime repair exonuclease 1 (TREX1), transcript 2131 variant 5, mRNA. TREX1 NM 033629 Homo sapiens three prime repair exonuclease 1 (TREX1), transcript 2132 variant 4, mRNA. TREX1 NM 016381 Homo sapiens three prime repair exonuclease 1 (TREX1), transcript 2133 variant 1, mRNA. TRNT1 NM 182916 Homo sapiens tRNA nucleotidyl transferase 1 (TRNT1), transcript 2134 variant 1, mRNA. TTC7A NM 020458 Homo sapiens tetratricopeptide repeat domain 7A (TTC7A), transcript 2135 variant 2, mRNA. TYK2 NM 003331 Homo sapiens tyrosine kinase 2 (TYK2), mRNA. 2136 UNC119 NM 005148 Homo sapiens unc-119 lipid binding chaperone (UNC119), transcript 2137 variant 1, mRNA. UNC119 NM 054035 Homo sapiens unc-119 lipid binding chaperone (UNC119), transcript 2138 variant 2, mRNA. UNC13D NM 199242 Homo sapiens unc-13 homolog D (UNC13D), mRNA. 2139 UNC93B1 NM 030930 Homo sapiens unc-93 homolog B1 (C. elegans) (UNC93B1), mRNA. 2140 UNG NM 080911 Homo sapiens uracil DNA glycosylase (UNG), transcript variant 2, 2141 mRNA. UNG NM 003362 Homo sapiens uracil DNA glycosylase (UNG), transcript variant 1, 2142 mRNA. USP18 NM 017414 Homo sapiens ubiquitin specific peptidase 18 (USP18), mRNA. 2143 USP20 NM 006676 Homo sapiens ubiquitin specific peptidase 20 (USP20), transcript 2144 variant 1, mRNA. USP20 NM 001008563 Homo sapiens ubiquitin specific peptidase 20 (USP20), transcript 2145 variant 2, mRNA. USP20 NM 001110303 Homo sapiens ubiquitin specific peptidase 20 (USP20), transcript 2146 variant 3, mRNA. VAPA NM 003574 Homo sapiens VAMP associated protein A (VAPA), transcript variant 2147 1, mRNA. VAPA NM 194434 Homo sapiens VAMP associated protein A (VAPA), transcript variant 2148 2, mRNA. VCP NM 007126 Homo sapiens valosin containing protein (VCP), mRNA. 2149 VDAC1 NM 003374 Homo sapiens voltage dependent anion channel 1 (VDAC1), transcript 2150 variant 1, mRNA. VDAC1 NR 036624 Homo sapiens voltage dependent anion channel 1 (VDAC1), transcript 2151 variant 3, non-coding RNA. VDAC1 NR 036625 Homo sapiens voltage dependent anion channel 1 (VDAC1), transcript 2152 variant 2, non-coding RNA. VPS13B NM 017890 Homo sapiens vacuolar protein sorting 13 homolog B (yeast) 2153 (VPS13B), transcript variant 5, mRNA. VPS13B NM 181661 Homo sapiens vacuolar protein sorting 13 homolog B (yeast) 2154 (VPS13B), transcript variant 4, mRNA. VPS13B NM 015243 Homo sapiens vacuolar protein sorting 13 homolog B (yeast) 2155 (VPS13B), transcript variant 3, mRNA. VPS13B NR 047582 Homo sapiens vacuolar protein sorting 13 homolog B (yeast) 2156 (VPS13B), transcript variant 6, non-coding RNA. VPS13B NM 152564 Homo sapiens vacuolar protein sorting 13 homolog B (yeast) 2157 (VPS13B), transcript variant 1, mRNA. VPS45 NM 007259 Homo sapiens vacuolar protein sorting 45 homolog (VPS45), transcript 2158 variant 1, mRNA. WAS NM 000377 Homo sapiens Wiskott-Aldrich syndrome (WAS), mRNA. 2159 WEE1 NM 003390 Homo sapiens WEE1 G2 checkpoint kinase (WEE1), transcript variant 2160 l,mRNA. WEE1 NM 001143976 Homo sapiens WEE1 G2 checkpoint kinase (WEE1), transcript variant 2161 2, mRNA. WIPF1 NM 001077269 Homo sapiens WAS/WASL interacting protein family member 1 2162 (WIPF1), transcript variant 2, mRNA. WIPF1 NM 003387 Homo sapiens WAS/WASL interacting protein family member 1 2163 (WIPF1), transcript variant 1, mRNA. XIAP NM 001204401 Homo sapiens X-linked inhibitor of apoptosis, E3 ubiquitin protein 2164 ligase (XIAP), transcript variant 2, mRNA. XIAP NM 001167 Homo sapiens X-linked inhibitor of apoptosis, E3 ubiquitin protein 2165 ligase (XIAP), transcript variant 1, mRNA. XIAP NR 037916 Homo sapiens X-linked inhibitor of apoptosis, E3 ubiquitin protein 2166 ligase (XIAP), transcript variant 3, non-coding RNA. YBX1 NM 004559 Homo sapiens Y-box binding protein 1 (YBX1), transcript variant 1, 2167 mRNA. YWHAZ NM 001135699 Homo sapiens tyrosine 3-monooxygenase/tryptophan 5-monooxygenase 2168 activation protein zeta (YWHAZ), transcript variant 3, mRNA. YWHAZ NM 001135700 Homo sapiens tyrosine 3-monooxygenase/tryptophan 5-monooxygenase 2169 activation protein zeta (YWHAZ), transcript variant 4, mRNA. YWHAZ NM 001135701 Homo sapiens tyrosine 3-monooxygenase/tryptophan 5-monooxygenase 2170 activation protein zeta (YWHAZ), transcript variant 5, mRNA. YWHAZ NM 001135702 Homo sapiens tyrosine 3-monooxygenase/tryptophan 5-monooxygenase 2171 activation protein zeta (YWHAZ), transcript variant 6, mRNA. YWHAZ NM 003406 Homo sapiens tyrosine 3-monooxygenase/tryptophan 5-monooxygenase 2172 activation protein zeta (YWHAZ), transcript variant 1, mRNA. YWHAZ NM 145690 Homo sapiens tyrosine 3-monooxygenase/tryptophan 5-monooxygenase 2173 activation protein zeta (YWHAZ), transcript variant 2, mRNA. ZAP70 NM 001079 Homo sapiens zeta chain of T cell receptor associated protein kinase 70 2174 (ZAP70), transcript variant 1, mRNA. ZAP70 NM 207519 Homo sapiens zeta chain of T cell receptor associated protein kinase 70 2175 (ZAP70), transcript variant 2, mRNA. ZBTB24 NM 014797 Homo sapiens zinc finger and BTB domain containing 24 (ZBTB24), 2176 transcript variant 1, mRNA. ZBTB24 NM 001164313 Homo sapiens zinc finger and BTB domain containing 24 (ZBTB24), 2177 transcript variant 2, mRNA.

Table 12 lists all transcript variants for genes in Table 6 that were not ‘discovered’ by PBio on the basis of aCGH (CNV identified genes). The SEQ ID NOs correspond to transcript variants (oftentimes more than one per gene).

TABLE 13 Genes for which the total burden of heterozygous, damaging variants was found to be statistically greater in PML cases versus EXAC controls Ave Ave Ave FET Ave EXAC EXAC corr GENE CASES CASES SAMPLES Ave FET (419) Ave OR Ethnicity Overlap PLCG2 17 1,806 31,277 1.43E−10 6.21E−08 10.27 EUR EUR + AFR RBCK1 6 187 29,324 4.27E−07 1.86E−04 24.60 EUR EPG5 9 764 32,835 7.11E−07 3.09E−04 10.79 EUR IL17F 4 61 33,346 1.67E−06 7.28E−04 54.57 EUR SHARPIN 8 646 32,162 2.58E−06 1.12E−03 10.84 EUR PRF1 8 715 33,027 4.44E−06 1.93E−03 10.04 EUR JAGN1 5 163 27,768 6.80E−06 2.96E−03 21.71 EUR TAN 5 203 28,125 1.80E−05 7.82E−03 17.63 EUR POLE 11 1,660 29,108 2.84E−05 1.23E−02 5.51 EUR EUR + AFR LRBA 11 1,876 32,136 3.47E−05 1.51E−02 5.38 EUR EHF 3 49 32,588 4.83E−05 2.10E−02 48.59 EUR IL12B 3 58 33,112 7.44E−05 3.23E−02 41.70 EUR ATL2 8 31 5,041 4.03E−11 1.75E−08 90.11 AFR NHEJ1 6 27 4,384 5.48E−09 2.39E−06 64.56 AFR LYST 11 291 4,748 1.09E−08 4.76E−06 16.85 AFR H1VEP1 9 150 4,432 7.41E−08 3.22E−05 23.83 AFR AP3B1 5 46 4,937 1.69E−06 7.36E−04 33.23 AFR TNFRSF10A 7 149 4,626 3.28E−06 1.43E−03 15.03 AFR PlK3CD 7 148 4,549 3.52E−06 1.53E−03 14.87 AFR PLCG2 8 256 4,410 1.47E−05 6.41E−03 9.99 AFR EUR + AFR PNP 3 11 5,189 2.00E−05 8.69E−03 78.45 AFR POLE 8 297 4,752 2.48E−05 1.08E−02 9.23 AFR EUR + AFR MCEE 3 13 5,164 3.10E−05 1.35E−02 66.04 AFR DOCK2 6 173 5,023 6.39E−05 2.78E−02 11.21 AFR ALG12 4 43 4,252 6.73E−05 2.93E−02 23.03 AFR

Table 13 lists genes for which the total burden of heterozygous, damaging variants was found to be statistically greater in PML cases versus ExAC controls. Gene burden analysis was performed as described below at minor allele frequency (MAF) cutoffs of 0.01, 0.02, 0.03, 0.04 and 0.05. Not all genes survived statistical analysis at all MAF cutoffs. For each gene that survived at multiple MAF cutoffs, the averages of the Fisher's Exact Test (FET), nominal and corrected, were calculated, as were the other relevant metrics. Two genes overlapped between AFR and EUR analyses. FETs were corrected for multiple testing with the number of genes used in this study (419). Only genes for which FET corr was <0.05 and in which variants affected >10% of cases within the given ethnicity (>2 for AFR, >4 for EUR) were considered for inclusion.

TABLE 14 Top tier of variants found to be significant on the basis of variant burden analysis PML PML PML ExA ExA PML PML PML PML PML PML Variant Geno- EUR AFR LAT ExAC C C EUR EUR AFR AFR ALL ALL Gene (hg19) type 44 21 5 EUR AFR LAT OR FET OR FET OR FET PLC chr16:81942175, het 2 5 0 512/32281 88/47 07 116/5548 2.95 0.154755 16.40 0.0000 6.49 0.0002 G2 A > G IFIH chr2:163136505, het 6 1 0 611/33155 23/5182 119/5671 8.41 0.000156 11.22 0.0927 6.38 0.0002 1 C > G TCI chr11:67818269, het 0 4 0 103/33193 200/5170 60/5770 NA NA 5.85 0.0082 7.31 0.0028 RG1 G > A IGL chr22:23917192, het 4 3 1 751/33348 603/5183 236/5782 4.34 0.017218 1.27 0'7286 3.47 0.0036 Ll G > T MA chr20:3846397, hom 4 4 0 800/32122 684/4982 52/5691 3.92 0.023868 1.48 0.5191 3.47 0.0036 VS C > T SHA chr8:145154222, het 8 4 0 2916/33177 59/4865 171/5780 2.31 0.053526 19.17 0.0001 2.68 0.0040 RPI G > A N CHD chr8:61654298, het 5 0 0 1103/ 33106 39/4840 93/5725 3.72 0.015268 NA NA 2.64 0.0485 7 T > A CX3 chr3:39323163, hom 11 4 0 4723/31219 193/4376 1357/5491 1.87 0.088087 5.10 0.0128 1.51 0.1806 CR1 A > C LRB chr4:151199080, hom 3 3 0 2260/33328 20/5195 54/5785 1.01 1.000000 43.13 0.0001 1.69 0.2736 A G > A HIV chr1:42047208, het 5 3 1 3383/32494 123/5061 902/5756 1.10 0.803620 6.69 0 0143 1.30 0.4283 EP3 C > G IFIH chr2:163124051, hom 20 3 1 12107/33356 184/5199 1076/5776 1.46 0.212471 4.54 0.0374 1.21 0.4372 1 C > T RNA chr1:182554557, hom 7 2 0 4543/33356 78/5202 167/5785 1.20 0.658473 6.91 0.0403 1.22 0.5616 SEL C > T

Table 14 lists the top tier of variants that were found to be significant on the basis of variant burden analysis, as described below. For each variant (genome coordinates are based on UCSC hg19), detailed information is presented of the numbers of EUR and AFR cases that carry the variant, along with the ethnic-specific and aggregate statistical metrics.

TABLE 15 Second tier of variants found on the basis of variant burden analysis PML PML PML PML PML PML PML PML PML Variant Geno EUR AFR LAT ExAC ExAC ExAC EUR EUR AFR AFR ALL ALL Gene (hg19) type 44 21 5 EUR AFR LAT OR FET OR FET OR FET SHA chr8:145154824, het 3 0 0 2/30,670 0/4,471 0/5,302 1122.00 0.000000 NA NA 905.40 0.0000 RPIN A > C RTE chr:2062305450, het 0 2 0 1/32,552 0/4,838 0/5,737 NA NA 1240.64 0.0000 1268.41 0.0000 L1 C > T IGLL chr22:23915745, het 2 0 1 19/33,348 74/5,184 9/5,783 83.53 0.000351 NA NA 19.41 0.0006 1 G > A PGM chr6:83884161, het 0 2 0 0/33,069 26/5,167 3/5,748 NA NA 20.81 0.0055 44.58 0.0011 3 C > G ATM chr11:108202772, het 3 0 0 170/32,707 3/5,099 7/5,713 14.00 0.001636 NA NA 10.78 0.0032 G > T TME chr5:138856923, het 2 2 0 108/32,327 204/4,842 58/5,770 14.21 0.009863 2.39 0.2226 6.97 0.0033 M173 C > T CLC chr16:1510535, het 0 2 0 1/32,898 66/5,119 0/5,732 NA NA 8.06 0.0308 19.18 0.0055 N7 C > T MAV chr20:3843027, hom 4 2 0 803/33,206 167/5,171 46/5,779 4.04 0.021706 3.15 0.1480 3.98 0.0056 S C > A ORAI chr12:122064788, het 4 0 0 371/28,708 5/3,555 16/5,354 7.64 0.002562 NA NA 5.76 0.0064 1 G > GT RBF chr16:7714909, het 0 2 0 1/33,367 69/4,902 4/5,782 NA NA 7.37 0.0361 17.48 0.0066 OX1 C > T MAL chr18:56401523, het 4 0 0 466/33,239 9/5,179 40/5,760 7.03 0.003411 NA NA 5.14 0.0093 T1 C > T GFI1 chr1:92946625, het 2 1 0 206/29,111 6/4,156 39/5,114 6.68 0.039391 34.58 0.0347 6.80 0.0113 G > C DOC chr5:169081453, het 0 2 0 48/33.350 43/5,201 27/5,786 NA NA 12.63 0.0137 11.02 0.0155 K2 G > C ATM chr11:108117787, het 2 0 0 93/33,256 2/5,151 28/5,756 16.98 0.007047 NA NA 10.53 0.0169 C > T SNA chr22:21235389, het 3 0 0 283/32,917 21/5,149 32/5,740 8.44 0.006584 NA NA 5.79 0.0171 P29 A > G TICA chr19:4817657, het 0 2 0 32/31,437 71/4,814 19/5,687 NA NA 7.03 0.0392 10.08 0.0183 M1 C > T GTP chr10:1060218, hom 3 0 0 334/33,367 20/5,202 21/5,786 7.24 0.009925 NA NA 5.25 0.0220 BP4 G > A BAC chr21:30698953, het 2 0 0 134/33,122 4/5,103 6/5,778 11.72 0.014110 NA NA 8.96 0.0227 H1 T > G DOC chr9:304628, het 2 0 0 149/33,298 2/5,161 5/5,762 10.59 0.017020 NA NA 8.31 0.0261 K8 G > A STX chr19:7712287, het 2 0 0 161/32,104 4/4,626 11/5,686 9.45 0.021028 NA NA 7.06 0.0350 BP2 G > C FAS chr10:90771767, het 2 0 0 175/33,304 3/5,182 10/5,731 9.01 0.022902 NA NA 6.89 0.0365 G > A GOL chr3:121415370, het 3 2 0 1,111/ 26/5,179 84/5,779 2.12 0.180743 20.86 0.0055 2.71 0.0443 GB1 T > C 33,349 FUK chr16:70503095, het 4 0 0 741/33,341 23/4,899 73/5,787 4.40 0.016488 NA NA 3.13 0.0449 A > G IL10 chr1:206945738, het 2 0 0 206/33,343 2/5,198 6/5,787 7.66 0.030787 NA NA 6.06 0.0458 C > T ITK chr5:156593120, het 2 0 0 206/33,353 5/5,203 5/5,789 7.66 0.030770 NA NA 6.01 0.0466 C > T STIM chr4:27019452, het 2 0 0 219/33,369 5/5,202 9/5,789 7.21 0.034346 NA NA 5.57 0.0532 2 C > T ASH chr1:155317682, het 2 0 0 218/33,367 2/5,203 17/5,789 7.24 0.034067 NA NA 5.48 0.0548 1L C > T TBC1 chr17:77926526, het 3 0 0 496/31,905 15/4,845 21/5,707 4.63 0.031269 NA NA 3.53 0.0584 D16 C > T LYS chr1:235840495, het 3 0 0 517/33,239 10/5,156 35/5,756 4.63 0.031299 NA NA 3.47 0.0606 T G > T SAL chr14:21993359, het 3 0 0 519/31,729 14/4,520 17/5,718 4.40 0.035528 NA NA 3.37 0.0650 L2 G > A CHD chr8:61757805, het 3 0 0 517/32,880 14/4,872 41/5,765 4.58 0.032169 NA NA 3.36 0.0654 7 C > T BLM chr15:91306241 het 2 0 0 266/33,277 10/5,061 17/5,756 5.91 0.048875 NA NA 4.40 0.0799 G > A NOD chr16:50741791, het 0 2 0 285/33,369 21/5,203 2/5,789 NA NA 25.97 0.0037 4.21 0.0860 2 C > T IGLL chr22:23915583, het 2 0 0 265/33,334 21/5,183 26/5,787 5.94 0.048403 NA NA 4.15 0.0881 1 T > C TTC7 chr2:47205921, het 3 0 0 589/33,202 13/5,173 61/5,759 4.05 0.043427 NA NA 2.94 0.0891 A C > T KITL chr12:88900891, het 4 0 0 1,023/ 31/5,158 40/5,760 3.15 0.046244 NA NA 2.38 0.0964 G C > A 33,226 ATR chr3:142281353, het 4 0 0 1,037/ 14/5,130 69/5,785 3.12 0.047671 NA NA 2.33 0.1021 C > G 33,343 ATM chr11:108123551, het 0 2 0 217/29,921 66/4,955 40/5,425 NA NA 7.80 0.0327 3.64 0.1093 C > T CR2 chr1:207641950, het 0 2 0 391/33,363 19/5,203 8/5,754 NA NA 28.72 0.0031 3.09 0.1422 C > T HIVE chr6:143092151, het 3 2 0 1,718/ 50/4,901 209/5,788 1.35 0.494339 10.21 0.0202 1.64 0.2458 P2 T > C 33,370 ITSN chr2:24431184, hom 3 2 0 2,019/ 17/5,186 55/5,784 1.14 0.748301 32.01 0.0025 1.55 0.3862 2 C > T 33,339 ITSN chr2:24432937, hom 3 2 0 2,026/ 17/4,958 56/5,672 1.10 0.753875 30.59 0.0028 1.50 0.3937 2 C > T 32,472 DOC chr9:312134, het 3 2 0 2,114/ 79/5,180 161/5,768 1.08 0.757661 6.80 0.0415 1.37 0.4238 K8 G > A 33,251 VPS1 chr8:100205255, het 0 2 0 811/33,345 19/5,192 100/5,778 NA NA 28.66 0.0031 1.37 0.6600 3B G > A NRIP chr21:16339852, het 0 2 0 901/33,355 19/5,203 64/5,780 NA NA 28.72 0.0031 1.30 0.6698 1 T > C

Table 15 lists the second tier of variants that were found on the basis of variant burden analysis, as described below. For each variant (genome coordinates are UCSC hg19), detailed information is presented of the numbers of EUR and AFR cases that carry the variant, along with the ethnic-specific and aggregate statistical metrics.

TABLE 16 Potential testing scenario, based on top variant burden hits Proportion Patient information Gene/ Cases of Cohort Test Primary Eth- Gen- Variant solved (n = 70) Method disease nicity der All 4 SNVs 28 40% genotyping M, H, O A, E both SHARPIN, 24 34% genotyping M, H, O A, E both IFIH1, PLCG2 SNVs IFIH1, PLCG2, 13 19% genotyping M, H, O A, E both SNVs SHARPIN SNV 13 19% genotyping M, H A, E both IFIH1 SNV 7 10% genotyping M, H, O A, E both PLCG2 SNV 7 10% genotyping M, H A, E both CHD7 SNV 5  7% genotyping M, H, O E both

Table 16 lists a potential testing scenario, based on top variant burden hits (reported in Table 14). The analysis is for illustrative purposes only, it being acknowledged that greater diagnostic yields can be obtained by assaying for a larger number of variants, including those listed in Table 15. Examples are given for diagnostic yield using singleton variants, as well as a variety of combinations, including the use of the top 4 variants. For this set of variants, the test method is described as genotyping, as opposed to whole gene sequencing (e.g., determination of the status at each of the bases, which yields a binary output, as opposed to identification of variants elsewhere in the relevant genes).

TABLE 17 Potential testing scenario using genes identified as having a greater burden of damaging, heterozygous variants in the PML cohort Ave Ethnic-Specific Overall Yield (Eur + Afr) Gene Cases Ethnicity Yield (%) (%) Test Method PLCG2 17/44 EUR 38 38 Gene sequencing PLCG2  8/21 AFR 38 Gene sequencing POLE  8/21 AFR 38 Gene sequencing POLE 11/44 EUR 25 29 Gene sequencing LRBA 11/44 EUR 25 Gene sequencing EPG5  9/44 EUR 20 Gene sequencing SHARPIN  8/44 EUR 18 Gene sequencing

Table 17 lists a potential testing scenario using genes identified as having a greater burden of damaging, heterozygous variants in the PML cohort (see Table 13). The nature of the testing method is ‘gene sequencing’ since the variants are not known in advance—any and all potentially damaging variants need to be considered in such an assay.

TABLE 18 Summary of genes that survive case-level, gene burden and/or variant burden analyses Gene Case Level Variant Burden Gene Burden PLCG2 Yes Yes Yes CHD7 Yes Yes IFIH1 Yes Yes AP3B1 Yes Yes EPG5 Yes Yes PIK3CD Yes Yes LRBA Yes Yes SHARPIN Yes Yes

Table 18 represents a summary of genes that survive case-level (2 or more examples in Tables 7, 8), gene burden and/or variant burden analyses (based on Tables 13 and 14). Of note is that PLCG2 satisfies all 3 criteria (2 or more examples, in Table 8, presence in Tables 13, 14). This summary demonstrates that many genes have been identified as significant on the basis of independent analysis methods.

Example 11—Figures Referenced in this Study

FIGS. 1-12 represent example CNV data from the PML gene discovery study (71 PML cases, see Table 7 for patient information) using array CGH (methods described herein). In each figure/drawing: 1) genome coordinates are listed at the top (hg18 assembly, chromosome number and position depicted); 2) data track 1 (labeled ‘Genes’) depicts the location of the RefSeq genes (exons are dark gray portions of the bars, introns are light gray portions of the bars); 3) data track 2 (labeled ‘Normal Cohort’) depicts the size and location of CNVs found in the NVE cohort (PBio's proprietary control database consisting of CNV findings in apparently healthy—e.g. normal—subjects, see methods herein) with the y-axis corresponding to the number of NVE subjects that have the CNV; and 4) remaining data tracks are CNV data found in individual PML patients wherein the y-axis corresponds to the log 2 ratio (see methods herein), points represent individual probes on the microarray, and line segments are shifted positive (copy number gain) or negative (copy number loss) based on the output of DNAcopy, the CNV calling algorithm. Typical log 2 ratios for gains and losses on the Agilent 1M microarray (see methods herein) and our experimental protocols are: 0.6 for duplications, 1.0 for triplication (or homozygous duplications), −1.0 for heterozygous deletions, and <−2 (often −4.0 to −6.0) for homozygous deletions. Relevant genes are labeled in the ‘Genes’ data track.

FIG. 1 represents an example of a gene impacted by germline and acquired CNVs. Germline CNVs that impact the PRKCB gene include patient PML50 with a 4.8 Kb intronic heterozygous loss (also found in 7 Normal subjects) and patient PML11 with a 7.3 Kb intronic gain (also found in 1 Normal subject). Acquired CNVs were found in 6 PML patients, a series of gains at −23.9 Mb with varying log 2 ratios, suggestive of a mixed cell population (array CGH experiments were performed on blood-derived genomic DNA).

FIG. 2 represents an example of potentially PML-relevant genes (TNFRSF13C and CENPM) impacted by acquired CNVs. Acquired CNVs were found in 9 PML patients, a series of gains at ˜40.6 Mb with varying log 2 ratios, suggestive of a mixed cell population (array CGH experiments were performed on blood-derived genomic DNA). All 9 PML patients (see Table 7 for patient information) had a primary diagnosis of HIV and were mixed gender (3 females and 6 males) and ethnicity (4 African ancestry and 5 European ancestry).

FIG. 3 represents an example of a gene impacted by CNVs. A 7.2 Kb intronic heterozygous loss (not found in Normal subjects, but an adjacent loss is found in 8 Normal subjects) that impacts the PKHD1 gene, was detected in patient PML26. CNVs were found in 3 PML patients, a series of gains at ˜51.9 Mb with varying log 2 ratios, suggestive of a mixed cell population (array CGH experiments were performed on blood-derived genomic DNA).

FIG. 4 represents an example of a gene impacted by a CNV loss. The 14.7 Kb intronic deletion impacts the BMPR2 gene. Heterozygous deletions were detected in patients PML58 and MVGS811-13a (also found in 2 Normal subjects), and a homozygous deletion was detected in patient PML29 (none found in Normal subjects). All three PML patients are males and their primary disease is HIV (see Table ⁷).

FIG. 5 represents an example of a gene impacted by a CNV gain. The 10.2 Kb exonic gain disrupts the COMMD6 gene. Two PML patients, PML29 and MVGS811-13a, have a homozygous duplication (log 2 ratio comparable to triplications) based on the observation that 1000 genomes subjects are reported to have this gain (see hg19 assembly DGV variant esv3632749, which reports 148 of 2504 subjects as having this gain; no Normals were found in PBio's NVE db). Both PML patients are males and their primary disease is HIV (see Table 7).

FIG. 6 represents an example of a gene impacted by a CNV gain. The 27.4 Kb exonic gain disrupts the KCTD7 gene and the right breakpoint is 16-90 Kb upstream of RABGEF1 transcript variants (RefSeq: NM 001287060, NR 104676, NM 014504, NM 001287062, NM 001287061). Patient PML29 has a homozygous duplication (log 2 ratio comparable to triplications) based on the observation that 1000 genomes subjects are reported to have this gain (see hg19 assembly DGV variant esv3613515, which reports 28 of 2504 subjects as having this gain; no Normals were found in PBio's NVE db). Patient PML63 has a duplication. Both PML patients are males of African ancestry and their primary disease is HIV (see Table 7).

FIG. 7 represents an example of a gene impacted by a CNV gain. The 344 Kb exonic gain disrupts the FPR2 and ZNF616 genes (via left and right breakpoints) and additional genes fully encompassed by this CNV are: FPR3, ZNF350, ZNF350-AS1, ZNF432, ZNF577, ZNF613, ZNF614, ZNF615, ZNF649, ZNF649-AS1, ZNF841. Patient PML03 has a homozygous duplication (log 2 ratio comparable to triplications) based on the observation that 3 Normal subjects (PBio's NVE db) are found to have a duplication of this region, along with patient PML10. Both PML patients are females of European ancestry and their primary diseases are HIV and MS (see Table 7).

FIG. 8 represents an example of a gene impacted by a CNV loss. The 1.1 Kb exonic deletion impacts the PIK3CD and PIK3CD-AS1 (previous gene symbol was C1orf200) genes. A homozygous deletion was detected in patient MVGS811-13a and this loss (heterozygous or homozygous) was not found in Normal subjects or the DGV public CNV database. The PML patient is a male and his primary disease is HIV (see Table 7). He is presumed to be of EUR ancestry (ethnicities were not available for MVGS samples).

FIG. 9 represents an example of a gene impacted by an intergenic CNV gain. The 16.7 Kb intergenic gain has a left breakpoint that is 105 Kb upstream of the CD180 gene (RefSeq transcript variant NM 005582). Patient MVGS995-4a has a homozygous duplication (log 2 ratio comparable to triplication) based on the observation that 1000 genomes subjects are reported to have this gain (see hg19 assembly DGV variant esv3605336, which reports 2 of 2504 subjects as having this gain; no Normals were found in PBio's NVE db). The PML patient is a male of European ancestry and his primary disease is MS (see Table 7).

FIG. 10 represents an example of a gene impacted by an intergenic CNV loss. The 7.7 Kb intergenic homozygous deletion has a left breakpoint that is 3-4 Kb upstream of VDAC1 transcript variants (RefSeq: NM 003374, NR 036625, NR 036624). This loss (heterozygous or homozygous) was not found in Normal subjects or the DGV public CNV database. Patient PML30 is a male of European ancestry and his primary disease is HIV (see Table 7).

FIG. 11 represents an example of a gene impacted by an intergenicCNV loss. The 6.8 Kb intergenic homozygous deletion has a left breakpoint that is 4 Kb downstream of EGR1 transcript variant (RefSeq: NM 001964) and 26 Kb downstream of ETF1 transcript variants (RefSeq: NM 001256302, NM 004730, NM 001282185, NM 001291975, NM 001291974). This loss was found to be homozygous in 1 Normal subject and the loss was also reported in the DGV public CNV database (see hg19 assembly DGV variant esv3606925, which reports 33 of 2504 subjects as having this loss, homozygous vs. heterozygous subjects are unknown). Patient PML69 is a male of European ancestry and his primary disease (condition) is kidney transplant (see Table 7, reported as ‘Other’). Patient PML69 was treated with CTLA4-Ig (belatacept, a CD28-B7 costimulation blocker and T-cell anergy inducer). The CD28 pathway includes links to the patient's genetic finding (e.g., homozygous deletion adjacent to the EGR1 gene) and several other genes that may be related to immunodeficiency (e.g., CD40LG, ITK, LCK, LRBA, PIK3CD, PIK3R1, PLCG2, WAS, and ZAP70) (Dekeyser M et al. Open Forum Infect Diseases, 2016, Refractory T-Cell Anergy and Rapidly Fatal Progressive Multifocal Leukoencephalopathy following Prolonged CTLA4 Therapy).

FIG. 12 represents an example of a gene impacted by an intergenic CNV loss. The 5.6 Kb intergenic homozygous deletion has a left breakpoint that is 20 Kb upstream of ITSN2 transcript variants (RefSeq: NM 019595, NM 006277, NM 147152). Heterozygous losses were found in 50 Normal subjects and the loss was also reported in the DGV public CNV database (see hg19 assembly DGV variant esv3590068, which reports 222 of 2504 subjects as having this loss, homozygous vs. heterozygous subjects are unknown). Patient PML65 is a male of African ancestry and his primary disease is HIV (see Table 7).

FIG. 13 represents an example of known and/or predicted protein interactions using the String database (string-db.org; see Szklarczyk et al., (2015) and references therein). A non-redundant list of all genes reported in Table 7 (43 genes, which included those whose expression was inferred to be impacted by a nearby intergenic CNV) as best solutions/explanations for 61 of 71 PML cases (11 PML cases are reported as ‘unsolved’, including 1 case for which only CGH data was obtained) was assessed using the String db. The ‘minimum required interaction score’ was set to ‘high confidence (0.7)’ and no additional ‘interactors’ were added. Of the 43 input genes, 21 were found to have high confidence interactions, as shown in the figure, along with annotation of the number of PML cases that had each of these genes as a solution/explanation (e.g., 3 PML cases in Table 7 were found to have a PLCG2 solution).

Example 12—Gene Burden Analysis

Gene burden analysis was performed as follows. Using a variety of in-house scripts, and data downloaded from ExAC (exac.broadinstitute.org), a count was performed for all variants occurring in each of the 419 genes listed in Table 6. Each variant was classified according to whether it was deemed damaging (on the basis of at least one of the prediction algorithms SIFT, PolyPhen2 or MutationTaster) or non-damaging, heterozygous or homozygous. This was performed in parallel for PML variants and those found in ExAC. ExAC data for which quality/coverage was <80% of expected was not used and gene burden analysis could not therefore be performed.

An ethnic-specific (EUR or AFR only, there were too few LAT cases for this type of analysis) comparison was then performed for each of 4 categories:

-   -   Homozygous damaging     -   Homozygous non-damaging     -   Heterozygous damaging     -   Heterozygous non-damaging

For all 4 categories, variants with minor allele frequency (MAF) cutoffs of 0.01, 0.02. 0.03. 0.04, 0.05 and 0.1 were considered.

For each comparison, odds ratios (OR) and Fisher's exact test (FET) were calculated for the comparison of numbers of PML cases with at least one variant of the type under consideration and those in ExAC. Correction for multiple testing was performed by multiplying the FET by the number of genes being considered (419). Only genes for whom the FET corrected was <0.05 were included in Table 13, which contains data on the average values for a given gene at all MAFs that passed FET correction. In practice, only the category of heterozygous damaging yielded significant genes.

Example 13—Variant Burden Analysis

For each variant identified in at least one PML case, a count was performed in order to obtain the frequency of the same variant in the cohort as a whole. This aggregate data was compared to counts for the same variant as reported in ExAC. ExAC data was filtered for quality/coverage and variant burden analysis was not performed if ExAC coverage was <80% expected.

Variant burden analysis was performed separately for EUR (n=44 cases) and AFR (n=21 cases) cohorts (LAT cohort was too small) and the OR and FET values calculated. From this analysis, only variants with OR>1 (e.g., potentially indicative of increased risk for PML) for both ethnicities (AFR and EUR) and for which the ExAC frequency of the variant was <5% were considered. Furthermore, only those variants for which the frequency in the ethnic-specific cohort was >10% (5 or more EUR cases, 3 or more AFR cases) were considered top-tier (Table 14), although other variants have been tabulated in Table 15.

Example 14—Exemplary PML Risk Prediction Tests

Table 16 provides exemplary markers for creating a low-cost, simple (genotype specific SNVs) PML risk prediction test. Other embodiments could be similarly devised from other SNVs reported in Tables 14 and 15. Different combinations of SNVs from Tables 14, 15 could be utilized in tests of varying complexity, to develop a test that would yield higher diagnostic yields than the top example listed in Table 16 (e.g., 40%).

Table 17 provides exemplary genes that could be included in a gene panel sequencing test for PML risk prediction. Other embodiments could be similarly devised from genes reported in Table 13, or from other tables disclosed herein.

Table 9 contains ‘example’ variants that may be considered as ‘AD’ causes of immunodeficiency (e.g., presence of just 1 of the 2 reported het SNVs in a given patient may be causing immunodeficiency), which may increase the risk for PML. For example, this may be a more likely scenario for het SNVs that are ‘novel’ in the ExAC db (e.g., not found in the general population), and even more likely if such novel SNVs are found in >=2 PML cases (irrespective of the invoked disease model). Examples of this include the following 3 genes:

-   -   AK2, 2 cases (Table 9), chr1:33476435, C>A, novel in ExAC PML20         and PML33, AFR and EUR, both HIV     -   EPG5, 2 cases (Table 9), chr18: 43445601, T>G, novel in ExAC         PML25 and PML27, both EUR, both HIV-TNFRSF11A, 9 cases (Table         7), chr18: 60052034, A>C, novel in ExAC, see Table 7 for case         IDs, 2 AFR and 7 EUR, all HIV

It can be appreciated by those skilled in the art that immunodeficiency genes presently known to cause AR disease may potentially cause AD disease. Numerous examples have been reported in the literature, including several of the genes listed in Table 6 (e.g., Disease model is indicated as AD AR for 32 genes, such as ADAR and TICAM1).

Example 15—Exemplary 96-Gene Panel PML Risk Prediction Tests

Table 19 contains an exemplary 96-gene panel based on genes that were found to have at least one PML case count from Tables 7 and 8. The “Genes” and “Case level solutions” columns showed genes and total number of PML cases (with at least one ‘case level’ solution) reported in Tables 7 and 8. In addition, the top 7 genes (CHD7, IFIH1, IGLL1, MAVS, PLCG2, SHARPIN, TCIRG1) from Table 14 with SNVs based on ‘PML ALL FET’ values <0.05 (column 0) were also included in Table 19. Among these 7 genes, 3 genes (IGLL1, MAVS, SHARPIN) with SNVs were based on ‘PML ALL FET’ values <0.05 (column 0) from Table 15.

TABLE 19 exemplary 96-gene panel Genes Case level solutions AP3B1 5 APOL1 1 ASH1L 1 ATM 1 ATR 3 BLM 1 CARD11 3 CDKN1B 1 CHD7 4 CLCN7 1 DCLRE1C 3 DDX58 1 DOCK8 8 EGR1 1 EPG5 3 ETF1 1 FPR2 1 GATA2 2 GFI1 4 HIVEP1 1 HIVEP2 2 HTR2A 1 IDO2 1 IFIH1 3 IFNGR2 1 IFNLR1 1 IGLL1 0 IKBKB 1 IL17F 1 IL1B 1 IL21R 1 IRAK4 2 ITSN2 2 JUN 2 KAT6B 1 KCTD7 1 LIG4 1 LRBA 1 MALL 1 MAPK3 2 MAVS 0 MCEE 1 MKL1 1 MYD88 1 NBN 1 NFKB1 3 NOD2 6 NRIP1 1 PIAS1 1 PIAS2 1 PIK3CD 4 PIK3CD-AS1 1 PIK3R1 1 PKHD1 3 PLCG2 5 PNPT1 1 POLA1 1 POLE 1 PRF1 1 PRKCB 1 PRKCD 1 PRKCH 1 PRKDC 4 PSTPIP1 1 PTEN 1 PTPRC 2 RABGEF1 1 RAD51 1 RAG1 4 RAG2 2 RIPK1 1 RIPK3 2 RNF168 2 RTEL1 2 SHARPIN 1 SKIV2L 1 SMAD4 1 STIM1 2 STIM2 1 STXBP2 3 TAP2 1 TBK1 2 TCIRG1 1 TICAM1 2 TLR3 2 TLR4 1 TNFRSF11A 10 TNFRSF13B 1 TNFRSF8 1 TP53 1 TRAF3 1 TRAFD1 1 TRPM2 1 VPS45 1 WEE1 2 ZAP70 3 TOTAL (96 genes) 172 Non-redundant cases 67 Dx yield for PML cohort (n = 70) 95.7%

The non-redundant number of PML cases and diagnostic yield are listed in the last 2 rows of Table 19. Specifically, a test including the 96 genes had a diagnostic yield of 95.7% based on the genetic findings from the 70 PML cases used in the present study.

Example 16—Exemplary 39-Gene Panel PML Risk Prediction Tests

Table 20 contains an exemplary 39-gene panel based on genes that were found to have multiple PML case count from Tables 7 and 8. The “Genes” and “Case level solutions” columns showed genes and total number of PML cases (with at least two ‘case level’ solutions) reported in Tables 7 and 8. In addition, the top 7 genes (CHD7, IFIH1, IGLL1, MAVS, PLCG2, SHARPIN, TCIRG1) from Table 14 with SNVs based on ‘PML ALL FET’ values <0.05 (column 0) were also included in Table 20. Among these 7 genes, 3 genes (IGLL1, MAVS, SHARPIN) with SNVs were based on ‘PML ALL FET’ values <0.05 (column 0) from Table 15.

TABLE 20 exemplary 39-gene panel Genes Case level solutions AP3B1 5 ATR 3 CARD11 3 CHD7 4 DCLRE1C 3 DOCK8 8 EPG5 3 GATA2 2 GFI1 4 HIVEP2 2 IFIH1 3 IGLL1 0 IRAK4 2 ITSN2 2 JUN 2 MAPK3 2 MAVS 0 NFKB1 3 NOD2 6 PIK3CD 4 PKHD1 3 PLCG2 5 PRKDC 4 PTPRC 2 RAG1 4 RAG2 2 RIPK3 2 RNF168 2 RTEL1 2 SHARPIN 1 STIM1 2 STXBP2 3 TBK1 2 TCIRG1 1 TICAM1 2 TLR3 2 TNFRSF11A 10 WEE1 2 ZAP70 3 TOTAL (39 genes) 115 Non-redundant cases 57 Dx yield for PML cohort (n = 70) 81.4%

The non-redundant number of PML cases and diagnostic yield are listed in the last 2 rows of Table 20. Specifically, a test including the 39 genes had a diagnostic yield of 81.4% based on the genetic findings from the 70 PML cases used in the present study.

Example 17—Exemplary 23-Gene Panel PML Risk Prediction Tests

Table 21 contains an exemplary 23-gene panel based on genes that were found to have multiple PML case count from Tables 7 and 8. The “Genes” and “Case level solutions” columns showed genes and total number of PML cases (with at least three ‘case level’ solutions) reported in Tables 7 and 8. In addition, the top 7 genes (CHD7, IFIH1, IGLL1, MAVS, PLCG2, SHARPIN, TCIRG1) from Table 14 with SNVs based on ‘PML ALL FET’ values <0.05 (column 0) were also included in Table 21. Among these 7 genes, 3 genes (IGLL1, MAVS, SHARPIN) with SNVs were based on ‘PML ALL FET’ values <0.05 (column 0) from Table 15.

TABLE 21 exemplary 23-gene panel Genes Case level solutions AP3B1 5 ATR 3 CARD11 3 CHD7 4 DCLRE1C 3 DOCK8 8 EPG5 3 GFI1 4 IFIH1 3 IGLL1 0 MAVS 0 NFKB1 3 NOD2 6 PIK3CD 4 PKHD1 3 PLCG2 5 PRKDC 4 RAG1 4 SHARPIN 1 STXBP2 3 TCIRG1 1 TNFRSF11A 10 ZAP70 3 TOTAL (23 genes) 83 Non-redundant cases 50 Dx yield for PML cohort (n = 70) 71.4%

The non-redundant number of PML cases and diagnostic yield are listed in the last 2 rows of Table 21. Specifically, a test including the 23 genes had a diagnostic yield of 71.4% based on the genetic findings from the 70 PML cases used in the present study.

Example 18—Exemplary 15-Gene Panel PML Risk Prediction Tests

Table 22 contains an exemplary 15-gene panel based on genes that were found to have multiple PML case count from Tables 7 and 8. The “Genes” and “Case level solutions” columns showed genes and total number of PML cases (with at least four ‘case level’ solutions) reported in Tables 7 and 8. In addition, the top 7 genes (CHD7, IFIH1, IGLL1, MAVS, PLCG2, SHARPIN, TCIRG1) from Table 14 with SNVs based on ‘PML ALL FET’ values <0.05 (column 0) were also included in Table 22. Among these 7 genes, 3 genes (IGLL1, MAVS, SHARPIN) with SNVs were based on ‘PML ALL FET’ values <0.05 (column 0) from Table 15.

TABLE 22 exemplary 15-gene panel Genes Case level solutions AP3B1 5 CHD7 4 DOCK8 8 GFI1 4 IFIH1 3 IGLL1 0 MAVS 0 NOD2 6 PIK3CD 4 PLCG2 5 PRKDC 4 RAG1 4 SHARPIN 1 TCIRG1 1 TNFRSF11A 10 TOTAL (15 genes) 59 Non-redundant cases 39 Dx yield for PML cohort (n = 70) 55.7%

The non-redundant number of PML cases and diagnostic yield are listed in the last 2 rows of Table 22. Specifically, a test including the 15 genes had a diagnostic yield of 55.7% based on the genetic findings from the 70 PML cases used in the present study.

Example 19—Exemplary 11-Gene Panel PML Risk Prediction Tests

Table 23 contains an exemplary 11-gene panel based on genes that were found to have multiple PML case count from Tables 7 and 8. The “Genes” and “Case level solutions” columns showed genes and total number of PML cases (with at least five ‘case level’ solutions) reported in Tables 7 and 8. In addition, the top 7 genes (CHD7, IFIH1, IGLL1, MAVS, PLCG2, SHARPIN, TCIRG1) from Table 14 with SNVs based on ‘PML ALL FET’ values <0.05 (column 0) were also included in Table 23. Among these 7 genes, 3 genes (IGLL1, MAVS, SHARPIN) with SNVs were based on ‘PML ALL FET’ values <0.05 (column 0) from Table 15.

TABLE 23 exemplary 11-gene panel Genes Case level solutions AP3B1 5 CHD7 4 DOCK8 8 IFIH1 3 IGLL1 0 MAVS 0 NOD2 6 PLCG2 5 SHARPIN 1 TCIRG1 1 TNFRSF11A 10 TOTAL (11 genes) 43 Non-redundant cases 33 Dx yield for PML cohort (n = 70) 47.1%

The non-redundant number of PML cases and diagnostic yield are listed in the last 2 rows of Table 23. Specifically, a test including the 11 genes had a diagnostic yield of 47.1% based on the genetic findings from the 70 PML cases used in the present study.

Example 20—Exemplary 10-Gene Panel PML Risk Prediction Tests

Table 24 contains an exemplary 10-SNV panel based on top 7 SNVs in Table 14 and 3 SNVs from Table 15 (based on overlapping genes between 14 and 15: IGLL1, MAVS, SHARPIN). Specifically, Using the top 10 SNVs (7 from Table 14, along with 3 from Table 15, residing in genes already selected from Table 14), an additive count (column “Case total additive (non-redundant)”) was performed to determine how many PML cases had at least one of the variants when these were considered in order (e.g., column “Order (FET)”: ‘1’, first, followed by ‘1’+‘2’, followed by ‘1’+‘2’+‘3’, etc). Since some individuals harbor more than one variant, the additive count is not equal to the simple sum of PML case numbers for each variant (column “Case total per SNV”). All genome coordinates are based on hg19 build.

An additive count was performed for ExAC subjects (column “ExAC subjects total additive (redundant)”), as follows: i) The average cohort size for ExAC for all variants was calculated; ii) Each total subject count (all ethnicities) was normalized to this average cohort size. The ExAC additive count represents a simple addition: labeled as “redundant” in column “ExAC subjects total additive (redundant)”, because information regarding the possible presence of multiple variants in the same individual is not available; iii) Odds Ratios (ORs) and Fisher's Exact test (FET) values were calculated (columns “PML ALL OR additive” and “PML ALL FET additive”).

TABLE 24 exemplary 10-gene panel Case Case total Dx ExAC PML PML total additive yield subjects ALL ALL Order Table Variant per (non- (non- total additive OR FET (FET)¹ source gene (hg19) Genotype SNV redundant)² redundant) (redundant)³ additive additive  1 14 PLCG2 chr16:81942175, A > G het 7 7 10% 730 6.50 2.00E−04  2 14 IFIH1 chr2:163136505, C > G het 7 13 19% 1,473 6.49 6.37E−07  3 14 TCIRG1 chr11:67818269, G > A het 4 16 23% 1,830 6.73 2.94E−08  4 14 IGLL1 chr22:23917192, G > T het 8 22 31% 3,388 5.42 9.41E−09  5 14 MAVS chr20:3846397, C > T hom 8 26 37% 4,947 4.60 2.13E−08  6 14 SHARPIN chr8:145154222, G > A het 12 33 47% 8,064 3.91 5.10E−08  7 14 CHD7 chr8:61654298, T > A het 5 36 51% 9,292 3.89 3.26E−08  8 15 SHARPIN chr8:145154824, A > C het 3 37 53% 9,294 4.12 8.10E−09  9 15 IGLL1 chr22:23915745, G > A het 3 38 54% 9,394 4.30 2.59E−09 10 15 MAVS chr20:3843027, C > A hom 6 38 54% 10,393 3.77 5.26E−08 ¹SNV order based on lowest FET value reported in Tables 14 and 15 for combined ethnicities ²PML case total = 70 ³ExAC subject total = 43,419 (average for the 10 SNVs)

It can be appreciated by those skilled in the art that the above gene panels were selected based on the present genetic findings in 70 PML cases. Furthermore, a gene not presently selected for any of these exemplary gene panels may be added to the gene panel. For example, genes in which only 1 PML case was found to have variants fulfilling the criteria may be added to the gene panel if genetic validation in additional PML cases shows a ‘n=1 case’ gene is impacted by more than 1 PML case when the data are examined for a new set of PML cases. In some cases, additional genes (e.g., PML-linked genes such as DOCK8, BAG3, STAT1) may be added to the gene panel.

Example 21—Identify Additional Genetic Variations

The methods and protocols described in the previous examples can be used to identify any possible genetic variations. Data can be generated by comparing genetic variations identified in 2 cohorts: 1) non-diseased cohort including 1000 non-diseased individuals (e.g., individuals without PML); and 2) diseased cohort including 100 diseased individuals (e.g., individuals with PML). The individuals in the cohorts can be gender and/or ethnically matched. The genetic variations present in the non-diseased cohort and diseased cohort can be identified using CNV analysis (e.g., described in Example 2) or whole exome sequencing (e.g., described in Example 3). Two new genetic variations, CNV 1 (located on gene #1) and CNV 2 (located on gene #2), are identified, for example, by comparing the sequence data with a reference sequence (e.g., UCSC hg19). Data from a CNV database created using genome-wide CNV data on healthy subjects (or individuals without PML) such as the Normal Variation Engine (NVE) described herein can be used to determine if a CNV found in a PML cohort occurs at higher frequency or not compared to the NVE. Similarly, SNVs identified in a PML cohort can be interpreted for the potential relevance to PML using the Exome Aggregation Consortium (ExAC) or Genome Aggregation Database (gnomAD) publicly available resources [Lek M et al. Nature. 2016 Aug. 18; 536(7616):285-91]; that is, to obtain frequency data (e.g., ethnic-specific frequency) for variants under consideration. In other embodiments, NVE databases for CNV assessment can be created for a variety of ethnicities (e.g., African and Latino ancestry subjects) to determine relevance of a CNV in a PML cohort compared to an ethnically matched CNV database on individuals without PML and/or using ethnic-specific data from publicly available CNV databases such as the Database of Genomic Variants [MacDonald J et al. Nucleic Acids Res. 2014 January; 42(Database issue):D986-92]. In one example, 20 out of the 100 diseased individuals have CNV 1, and only 10 out of the 1000 non-diseased individuals have CNV 1. In another example, 10 out of the 100 diseased individuals have CNV 2, and only 5 out of the 1000 non-diseased individuals have CNV 2. The p-value can be calculated using standard tests, such as the Fisher's Exact Test (FET) and data can be selected using certain significance value. For example, genetic variations with a p-value of less than 0.05 are included. Further, the frequency and odds ratio of the two genetic variations can be calculated and summarized in an exemplary table:

Genetic Frequency in Frequency in non- variation Genes diseased cohort diseased cohort OR CNV 1 Gene #1 20/100 = 20% 10/1000 = 1% (20/80)/(10/990) = 24.75 CNV 2 Gene #2 10/100 = 10%   5/1000 = 0.5%  (10/90)/(5/995) = 22.11

A subject without CNV 1, CNV 2, or both, may have a decreased risk of PML due to an infection of the brain by John Cunningham virus (JCV), and thus may be administered an immunosuppressive medication, such as natalizumab.

Other genetic variations such as SNV can be identify using the same method as described above.

Example 22—Analysis of the PML Cohort Array CGH Data for Additional CNVs

The array CGH data on the 71 PML cases was assessed (70 of 71 cases have array CGH and WES data, but PML67 only has array CGH data) to identify recurrent CNVs meeting the criteria of an OR>=3 and a FET<=0.05. The benefit of looking at higher frequency, recurrent CNVs is that PML risk can be easily assessed with PCR based, high-throughput screening methods that are also cost-effective. More frequent CNVs also have the potential to identify increased risk for PML in a larger proportion of patients, similar to the variant burden SNVs reported in multiple PML cases (e.g., Tables 14, 15, 38, and 39). For example, a genetic variant panel test for identifying a patient's risk of developing PML might contain one or more CNVs from Tables 1 or 28A and/or one or more SNVs from Tables 14, 15, 34, or 35.

Four recurrent losses of potential relevance in assessing PML risk were found and are reported in Table 28A (GRCh36/hg18 genome coordinates), three of which are also reported in Table 28B. One loss impacts exonic regions of CFHR1 and CFHR3 (SEQ ID 2200) and two other losses occur in intronic regions of the genes FUT8 (SEQ ID 2203) and ZBTB20 (SEQ ID 2202). The fourth loss is intergenic (SEQ ID 2201) and is located between two Ensembl genes (GRCh37/hg19 genome assembly): ENSG00000229703 (Ensembl transcript variant ENST00000437830, which overlaps RefSeq gene LOC101928226 and its corresponding RefSeq transcript NR 125950.1) and ENSG00000232694 (Ensembl transcript variant ENST00000436484). While the intergenic deletion may be impacting the expression of one or both adjacent genes (e.g., via loss of a transcription factor binding site), those skilled in the art will also consider whether long-range interactions are involved such that expression levels of genes located further away are modulated up or down (e.g., see Mifsud B et al. 2015, PMID 25938943). Similarly, intronic variants may have a similar impact and there is also the possibility that genetic variants (SNPs/SNVs, CNVs, etc.) are not directly involved in modulating gene expression but are in linkage disequilibrium (LD) with other genetic variants that are directly causing an effect (e.g., such variants serve as tags of causal or protective variants).

It can be appreciated by those skilled in the art that genetic variants (CNVs, SNVs, etc.) can be found in multiple, independent studies and many are reported in public databases, such as the Database of Genomic Variants (MacDonald J et al. 2014, PMID 24174537), the Exome Aggregation Consortium (ExAC, see Lek M et al. 2016, PMID 27535533), and ClinVar (Landrum M et al. 2018, PMID 29165669). Recurrent CNVs (gains or losses), such as those reported in Table 28A (and a subset that are reported in Table 1), are often found to approximately match the chromosomal breakpoints for CNVs reported from the 1000 Genomes Consortium Phase 3 study (Mills R et al. 2011, PMID 21293372; 1000 Genomes Project Consortium 2015, PMID 26432245). Since the CGH array (Agilent, Santa Clara, Calif.; array design ID AMADID 021529) used for genome-wide detection of CNVs in the PML cases contains ˜1 million probes each spaced ˜3 Kb apart, the breakpoints can each map anywhere between the reported genomic locations of probes (Tables 1 and 28A) and the next nearest probe. Use of publically available CNV data is sometimes useful for mapping breakpoints via sequencing and designing assays when they are similar in size and location of the CNVs detected in an independent study. For example, the three recurrent CNVs reported in Table 28A are approximately the same and location as deletion reported in the 1000 Genomes Consortium Phase 3: SEQ ID 2200 is similar to esv3588469, SEQ ID 2201 is similar to esv3589567, SEQ ID 2202 is similar to esv3597466, and SEQ ID 2203 is similar to esv3634776.

Table 28B lists the CNV Subregion Numbers (SRN, numbers 364-366) for the three variants that are present as heterozygous and/or homozygous losses and pass statistical filters, as described below. For CNVs that are not identical, the CNV subregion corresponds to the overlapping portions with other CNVs. In the case of recurrent CNVs, the CNV subregion may be identical to the original CNV (e.g., as in Tables 28A and 28B). Table 28B also contains the OR and FET values in the comparison of the frequency of the CNV in NVE cases (e.g., control subjects that do not have PML) vs. PML cases. The NVE cohort size is 1,000 subjects (unaffecteds) and the PML cohort size is 71 patients (affecteds). All reported CNVs/CNV subregions in Table 28B had FET<0.004, which is well below the 0.05 cutoff filter that was applied for this analysis. The corresponding OR values for the heterozygous losses (het loss) were 3.61 to 32.62 and for the homozygous losses (hom loss) were 42.57 to 71.98, which all are greater than the OR cutoff of 3. Tables 29 and 30 contain the gene and transcript variant information for the Table 28A genes that are directly impacted by a CNV (FUT8 and ZBTB20) except for the CFHR1 and CFHR3 genes, which are reported on in Tables 31 and 32.

Immune Dysregulation Genes

Immune dysregulation disorders, which are one of the underlying factors of PML (Hatchwell E 2015, PMID 26029204), are caused by mutations in one or more genes. Numerous genes have already been reported in the literature (e.g., NCBI PubMed) or other public databases (e.g., OMIM) and new ones continue to be discovered. Consequently, a state-of-the-art comprehensive genetic risk prediction test for PML will periodically involve assessment of information in the field for newly reported immune dysregulation genes, as well as performing new discovery studies (e.g., using a CNV-based gene discovery approach, as described herein, on a new cohort of PML cases). Furthermore, newly discovered genes linked to a disease or condition are oftentimes independently validated by other studies. For example, in our first PML study, our discovery of a homozygous deletion (SEQ ID 1028) upstream of ITSN2 (GN 309) as a potential cause of a PML patient's underlying immunodeficiency condition was subsequently supported by evidence in a mouse model that this gene is involved in immune dysregulation (Burbage M et al. 2018, PMID 29337666).

Our original PML risk gene/variant discovery study involved assessment of a total of 435 genes (see Tables 3, 6, 25A, 25B, and 26). The published literature was reassessed for new genes that cause or contribute to immune dysregulation disorders and a curated list of 270 genes was assembled (see Table 31). For example, one source for new genes to consider in our PML cohort was derived from a December, 2017 update by the International Union of Immunological Societies (IUIS) on primary immunodeficiencies (Bousfiha A et al. 2017, PMID 29226301; Picard C et al. 2017, PMID 29226302), which described 334 genes linked to inborn errors of immunity and 137 of these were not included in our original gene lists (Tables 3, 6, 25A, 25B, and 26). Another source was a study of common variable immunodeficiency genes (CVID) and review of the literature (de Valles-Ibanez G et al. 2017, PMID 29867916), which described 92 genes and 40 were not included in our original list of 435 genes. Interestingly, 37 of these 92 genes were not included in the updated IUIS list (PMIDs 29226301 and 29226302), which underscores the importance of consulting multiple, independent sources when curating an updated list of new immune dysregulation genes to consider. One other major source of new genes that comprise our set of 270 genes was an exome sequencing study on patients with primary antibody deficiency (PAD), a frequent form of primary immunodeficiency (PID). This study (Abolhassani H et al. 2018, PMID 29921932) assessed 202 genes of which 76 genes were not included in our original set of 435 genes and 45 of the 202 genes were not included in the updated IUIS list (PMIDs 29226301 and 29226302). The role of complement genetics in immune dysregulation disorders has been discussed (Mayilyan K 2012, PMID 22773339). Some complement system genes were already assessed in our original set of PML genes (e.g., C1QA, C1QB, C1QC, C5AR1, CD55, CD59, CR2, and FCN3 listed in Table 6) and 30 new ones were included in the new set of immune dysregulation genes (Table 31, see genes annotated with PMID 22773339).

Since another key underlying factor of PML is infection with the JC virus (Hatchwell E 2015, PMID 26029204), we also reassessed the literature and other sources (e.g., interactions via the String db, Szklarczyk D et al. 2017, PMID 27924014) for JCV-related biology and corresponding genes. For example, this was previously done to identify candidate PML risk genes (e.g., as described by van der Kolk N et al. 2016, PMID 27042682) in which a subset was subsequently found to harbor rare variants in one or more PML cases in our study (see Table 27, JC virus biology column). This new assessment resulted in inclusion of 18 new genes that are linked to JCV biology: B2M, BRD4, CXCR3, CXCL10, HERCS, IFI35, IFIT2, IFIT3, IGHMBP2, MX1, MX2, OAS1, OAS2, OAS3, OASL, RELA, RSAD2, XAF1. Published source annotation for this set of genes are reported in Table 31. For example, the Type I interferon pathway, which was implicated as a factor in PML on the basis of genetic variants found in genes involved in the pathway (e.g., IFIH1 and MAVS) in our prior study of the 70 PML cases (e.g., see Table 27), was linked to JCV biology via String db analysis of other genes in the pathway (Assetta B et al. 2016, PMID 27381292). In another example, supporting biology for the OAS gene family was found in a study of HIV-associated neurocognitive disorder (HAND) patients (Puccini J et al. 2015, PMID 25834052; Sanfilippo C et al. 2018, PMID 28236279), which is another type of neurological disorder that can manifest in HIV patients (Kolson D 2018, PMID 28820724).

Potential links between Parkinson's Disease (PD) genes and PML were further explored since SNCA was in our first gene list (see Table 6) and our separate investigation of SNCA triplication breakpoints identified the HERCS and HERC6 genes as potentially relevant to PD (see Zafar F. et al. 2018, PMID 29928688; Im E et al. 2016, PMID 27534820). The potential overlap in pathological mechanisms between PML and PD is further underscored by the link of HERCS to JCV (Assetta B et al. 2016, PMID 27381292) and neuroinflammation in general (Gelders G et al. 2018, PMID 29850629). Our curation of independent PD studies (including our own) or review papers have now linked a total of 37 PD-related genes to our candidate PML genes: 16 genes (CXCL12, CXCR4, DDX58, IFIH1, IL1B, MAVS, MYD88, RAB7A, RABGEF1, RAG1, SNCA, SQSTM1, TBK1, TLR3, TLR4, TMEM173) in our original list of 435 genes (Table 6) and 21 genes (ATG9A, CCZ1, FIS1, HERCS, HERC6, IFIT1, IFIT2, IFIT3, LRRK2, MFN1, MFN2, MON1A, MON1B, PINK1, PARK2/PRKN, RABSA, RABSB, RABSC RSAD2, TBC1D15, TBC1D17) in our new list of 270 genes (Table 31). In addition to the previously mentioned PD citations (PMIDs 29850629 and 29928688), supporting literature for linking known and candidate PD genes to candidate PML genes include: Torres-Odio S et al. 2017, PMID 28768533; Yamano K et al. 2018, PMID 29360040; Paparisto E et al. 2018, PMID 29669830. In Table 31, the disease model for LRRK2 is listed as unknown since mutations in this gene are not presently known to cause an immunodeficiency disorder (e.g., it does not appear in the updated IUIS gene lists, see PMIDs 29226301 and 29226302). It is known to cause PD via an AD model but, without further studies, this cannot be assumed with respect to immune dysregulation in the context of other disorders. Interestingly, recent studies (e.g., see Yan R and Liu Z 2017, PMID 27830463; Lee H et al. 2017, PMID 28202666; Witoelar A et al. 2017, PMID 28586827; Hui K et al. 2018, PMID 29321258; Sheng D et al. 2018, PMID 29499195; Toledo Pinto T et al. 2018, PMID 29755459; Kim K et al. 2018, PMID 29760073) increasingly support a role for LRRK2 in immune function (e.g., Type I interferon pathway) and immune disorders (e.g., Crohn's disease and leprosy).

We also revisited the literature for any new findings related to genes in our original list of 419 candidate PML genes (Table 6) that were found to harbor genetics variants of interest in our original analysis of the array CGH CNV data and/or WES data on the 70 PML cases in our cohort. Supporting evidence (Magna M et al. 2014, PMID 24531836; Jiang R et al. 2014, PMID 25339669; Minguet S et al. 2017, PMID 28805811; Ratajczak M et al. 2018, PMID 29541038; Lee G et al. 2018, PMID 29674451) was found for TLR4-linked genes (CXCL12, CXCR4, MYD88) in our previous list of 435 genes (Table 6), plus two new genes (CAV1 and HMGB1) in our updated list of 270 genes (Table 31). Finally, MB21D1 (gene alias cGAS) was added to our updated gene list (Table 31) on the basis of its direct link to TMEM173 (gene alias STING), which was included in our original gene list (Table 6); for example, as highlighted in a recent review (Chen Q et al. 2016, PMID 27648547). Finally, ITSN1 was included in our list of 270 genes (Table 31) based on a supporting study (Burbage M et al. 2018, PMID 2933766), cited herein as supporting functional data for one of our CNV-discovered PML candidate genes (ITSN2), plus three other more recent studies (Alvisi G et al. 2018, PMID 29599122; Dergai O et al. 2018, PMID 29851086; Gryaznova T et al. 2018, PMID 29958948).

It is well appreciated by those skilled in the art that many common disorders have a genetic basis and can be caused by one (autosomal, X-linked dominant, or X-linked recessive) or two mutations (autosomal recessive) in a gene, and that the mutation(s) may occur in any one of numerous genes. Furthermore, an increasing number of genetic studies are revealing that a given disorder can be caused or modified (e.g., age of onset or severity) by multiple variants present within a patient's genome. For example, autism has been linked to the presence of two or more genetic variants (CNVs or SNVs) within an individual (Marshall C et al. 2008, PMID 18252227; Yuen R et al. 2015, PMID 25621899). Accumulating evidence suggests that a monogenic disease model for immune dysregulation also provides an incomplete explanation of the pathology. For example, de Valles-Ibanez et al. 2018 (PMID 29867916) discuss the importance of considering other disease models (e.g., oligogenic or polygenic), particularly since the majority of CVID patients remain undiagnosed despite genetic assessment with exome or whole genome sequencing approaches.

Based on advances in genetic sequencing technologies and rapidly growing disease gene lists, many genetic testing providers now use gene panel tests, which are used to assess and deliver clinical information only for the subset of genes that have been definitively reported to cause the disease. Gene panel tests can be performed by genome capture methods for just the genes of interest or by performing WES or WGS but only interpreting the relevant disease genes (e.g., an in silico capture of a subset of the genes in the human genome). It can be appreciated by those skilled in the art that a PML genetic risk prediction test will likely involve testing for deleterious genetic variants in several immune dysregulation genes and that new genes/variants may be added to the testing panel as new studies are reported on immune disorder patients and/or PML patients.

There are several genetic testing providers that now offer gene panel testing. An example of a commercial provider of several different disease gene panels is Invitae (San Francisco, Calif.). Given their experience with testing and interpretation of a wide variety of gene panels (e.g., inherited cancers, metabolic disorders, and cardiology disorders), we compared their set of immunology gene panels to our curated PML candidate gene lists (Tables 6 and 31) to determine if their existing gene panel could be one potential option for assessing the genetic risk of developing PML. As of June 2018, Invitae had a total of 210 genes in their immunology panels and 157 of these were already included in our first list of 435 PML candidate genes (Tables 3, 6, 25A, 25B, and 26) and 206 were present in IUIS's December, 2017 update on primary immunodeficiencies (Bousfiha A et al. 2017, PMID 29226301; Picard C et al. 2017, PMID 29226302). However, 3 genes (ACD, PMM2, and SLC7A7) in Invitae's immunology gene panels were not found in our CNV-based gene discovery studies or in the various curation resources described herein. Therefore, for completeness, we included these 3 genes in our updated panel of 270 genes (Table 31).

There are 9 genes in Table 31 that have had gene symbol changes since the PML WES data were generated, these are (current RefSeq gene symbol list first and WES data gene symbol second):

ADA2 CECR1 ADGRL2 LPHN2 CXCL8 IL8 FAAP24 C19orf40 NSMCE3 NDNL2 OTULIN FAM105B PRKN PARK2 STN1 OBFC1 WASHC5 KIAA0196

Transcript variants and SEQ ID numbers for the additional 270 immune dysregulation genes (Table 31) are reported in Table 32. No RefSeq transcript variants were found for the IGHM and IGKC genes, so these are omitted from Table 32.

Analysis of the PML Cohort WES Data for 270 Additional Immune Dysregulation Genes

Using our previous methods for mining genetic variants from WES data on 70 PML cases (described herein), we have identified several new variants in a subset of the 270 genes (see Tables 32-37, 38, and 39) that may be causing or contributing to a PML patient's immune-compromised condition. As was done for the original 435 immune dysregulation genes (Tables 3, 6, 25A, 25B, and 26), three types of genetic analysis methods were used for the new set of 270 genes (Table 31): 1) case-solving approach, 2) gene burden analysis, and 3) variant burden analysis. A total of 275 SNVs (see Table 33) in 113 of the 270 genes that were assessed were identified in the cohort of 70 PML cases.

The case-solving method, which involves assessing WES data for each PML patient for the presence of rare, deleterious SNVs in comparison to an unselected control set of WES data (publicly available data from the Exome Aggregation Consortium, exac.broadinstitute.org), was applied to all 70 PML cases for which WES data were collected (see Table 7 for Sample ID, Ethnicity, Gender, and Primary Disease for each case). In the first study of this cohort that involved assessment of 435 genes (Tables 3, 6, 25A, 25B, and 26), the case-solving findings were reported in Tables 7-10 wherein Table 7 reported the top genetic variation(s) and gene for each case on the basis of variant frequency (<1 in 100 frequency cutoff in comparison to the ExAC subjects) and the known biology of the gene at the time of the study. Additional potential solutions were reported in Tables 8-10. Given the growing evidence for multiple variants/genes causing or contributing to immune dysregulation, case-solving results for the 270 additional genes were partitioned into 4 tables as follows:

-   -   Table 34, SNVs (het, hom, or phased comp het) with a frequency         of <=1/1,000 ExAC subjects or are novel;     -   Table 35, SNVs (het, hom, or phased comp het) with a frequency         of <=1/100 but >1/1,000 ExAC subjects; Table 36, Un-phased het         SNVs with a potential compound heterozygous frequency of <=1/100         ExAC subjects (a subset may prove to be in trans with further         validation work);     -   wherein SNVs are referred to as heterozygous (het), homozygous         (hom), or compound heterozygous (comp het).

As before, the frequency information for each variant was assessed in an ethnic-specific manner (AFR, EUR, or LAT). Variants were excluded from the analysis if the allele number in the ExAC subjects for a given ethnicity was <75% of the maximal number (˜40,300 for AFR subjects, ˜41,300 for LAT subjects, or ˜66,500 for EUR subjects). An exception was made for variant CFHR3 chr1:196759282, C>T, which has lower AN but only in AFR ExAC subjects. Other studies have reported that a deletion impacting CFHR3 is present at higher frequency in African ancestry subjects (e.g., see Cantsilieris S et al. 2018, PMID 29686068).

We observed a recurrent CFHR3 deletion (˜56 Kb in size) in our NVE control subjects and PML cases that maps to: chr1:196742735-196799244 (GRCh37/hg19). Both heterozygous and homozygous losses were found but only the homozygous deletions found in PML cases are reported in Table 28A (SEQ ID 2200). The loss overlaps the 1000 Genomes Phase 3 deletion esv3588469 (˜80 Kb in size): chr1:196728877-196808865 (GRCh37/hg19). It is possible that these two deletions are the same, which can be verified by sequencing the breakpoints of the deletion found in our NVE controls and PML cases. We observed the CFHR3 deletion in the homozygous state in 52 NVE controls (all EUR ancestry) and 5 PML cases (2 AFR and 1 LAT ancestry). Furthermore, we found a CFHR3 hom SNV in our variant burden analysis (described herein, see Table 38). Give the high frequency of the deletion in the general population, it is possible that some individuals called as homozygotes for the SNV are compound heterozygotes for the SNV and the deletion. The nature of short read sequencing means that homozygosity for a variant is inferred if a) the data is of sufficient quality (sufficient number of reads present) and b) only one of the two possible sequences at a given base position is observed. However, if an individual has only one allele (the other having been deleted), there is only one possible ‘state’ at each given base. This is known as loss of heterozygosity and is distinct from homozygosity. For this reason, the analysis of the homozygous state for the SNV has to be treated cautiously. However, the compound heterozygous state (SNV plus deletion) may well result in the same functional consequences as the homozygous SNV. Further laboratory work would be required to deconvolute the genotypes in this cohort.

Interestingly, the CFHR3 deletion has been linked to atypical hemolytic uremic syndrome (aHUS), as described in a recent case report (Bitzan M. et al. 2018, PMID 29728803). Furthermore, a 2015 case report (Gomez-Cibeira E et al. 2015, PMID 26718572) links aHUS to PML. No genetic information was reported for this aHUS patient, but she developed PML after receiving eculizumab.

A recessive or dominant disease model was applied according to the information reported in Table 31. For genes that have an ‘unknown’ or ‘association’ entry, the disease model was assumed to be AD and/or AR. Furthermore, if an AD model is currently the standard for a given gene (e.g., in OMIM), we did not rule out the potential for an AR model. For example, MBL2 is reported in Table 31 as an AD model gene but Table 34 reports on a rare homozygous (om) SNV (amino acid change G57E) in the PML15 case. The frequency cutoff of <1 in 100 was relaxed for FAT4 SNV A807V (SEQ ID 3086) in Tables 35 and 36 since this variant is present as a solution for multiple PML cases (PML09, PML28, PML31, PML32, PML37, PML65) in Table 34. In instances wherein a PML case had 3 or more SNVs, the frequency calculations were as follows: a) for a hom SNV paired with multiple het SNVs (e.g., obligate comp hets), the pairwise frequency was calculated for the hom SNV and each het SNV, and b) for 3 or more het SNVs, pairwise frequency was calculated using the rarest SNV paired with each higher frequency SNV.

Gene and variant burden analyses were performed on the updated set of 270 genes (Table 31) according to the methods described herein for the original set of 435 genes (Tables 3, 6, 25A, 25B, and 26). The results are reported in the following tables:

-   -   Table 37, gene burden results (same criteria used to generate         the Table 13 results);     -   Table 38, variant burden results (same criteria used to generate         the Table 14 results);     -   Table 39, variant burden results (same criteria used to generate         the Table 15 results);

The top SNV in Table 38 is CFHR3 chr1:196759282, C>T (rs138675433 in dbSNP build 150). The genotype is homozygous in 3 AFR and 3 EUR ancestry PML cases. Therefore, we have found a homozygous deletion (SEQ ID 2200) and a homozygous SNV (SEQ ID 3025) impacting the CFHR3 gene. Both the deletion and SNV are present at higher frequency in AFR ancestry subjects. Therefore, genotyping both variants in control subjects and PML patients of different ancestries will help define their role in increasing or decreasing PML risk. This is potentially highly relevant in light of a PML case report on a patient that had aHUS (Gomez-Cibeira E et al. 2015, PMID 26718572) and the link between aHUS and the CFHR3 gene (Pouw R et al. 2018, PMID 29740447).

Genetic findings in the first set of 435 genes for the 70 PML cases were summarized in a variety of formats (see Tables 7-10 and 13-27). Genetic findings in the updated set of 270 genes are summarized in Table 40 for all three analysis methods. For some PML cases, an SNV can appear in more than one case solving table (Tables 34-36), such as when an ‘unknown’ disease model gene has 2 or more SNVs and a given SNV is ascribed an AD model solution and an AR model solution. However, the total PML case counts in Table 40 correspond to a non-redundant number of PML cases to accurately reflect the total number of potentially solved PML cases per gene.

One of the top genes summarized in Table 40 is FAT4, which is the only gene that has genetic findings reported for all three types of analysis (case-solving, gene burden, variant burden) as reported in Tables 34-39. The FAT4 gene also has the highest number of potentially solved PML cases, 23 solutions based on Tables 34-36. Other genes with a higher number of case-solving solutions are: PRRC2A (22 solutions), MSHS (9 solutions), LRRK2 (8 solutions), and MX1 (8 solutions). Autosomal recessive mutations in the FAT4 gene (OMIM 612411) are involved in two disorders: Hennekam lymphangiectasia-lymphedema syndrome 2 (OMIM 616006) and Van Maldergem syndrome 2 (OMIM 615546). Hennekam lymphangiectasia-lymphedema syndrome 2 is of particular interest since a clinical feature of these patients is intestinal lymphangiectasia, which has been reported in a case of PML (Gomez-Cibeira E et al. 2015, PMID 26718572), which is also noted herein for the link to the CFHR3 gene via the PML patient's aHUS condition.

Another top gene in Table 40 is LRRK2, which has 8 solutions based on Tables 34-36 and was significant in gene burden analysis (Table 37). LRRK2 variants (e.g., the G2019S gain-of-function mutation) were initially found to cause or contribute to Parkinson's Disease (PD), but additional studies have linked the LRRK2 gene to immune function and disorders, as reported herein and in Table 31 (see PMID citations). We also found a subset of PML patients harboring a pair of LRRK2 SNVs (N299K, also known as N551K, SEQ ID 3192; R1398H, SEQ ID 3197), with heterozygous or homozygous genotype (see Tables 34 and 35), that are reported to be protective against PD (e.g., see Ross 0 et al. 2011, PMID 21885347; Heckman M et al. 2014, PMID 23962496; Heckman M et al. 2016, PMID 27521182). Whether one or both variants modify PML risk will require further studies.

TABLE 28A SEQ ID 2200-2203, four recurrent CNVs Original Original PML RefSeq CNV Original CNV CNV Case Gene SEQ Chr Start CNV Stop Size Type ID Symbol ID 1 195009358 195065867 56509 hom loss 3143 CFHR1, 2200 CFHR3 1 195009358 195065867 56509 hom loss 3159 CFHR1, 2200 CFHR3 1 195009358 195065867 56509 hom loss 3193 CFHR1, 2200 CFHR3 1 195009358 195065867 56509 hom loss 3202 CFHR1, 2200 CFHR3 1 195009358 195065867 56509 hom loss 3273 CFHR1, 2200 CFHR3 1 246933929 246940630 6701 het loss 3009 2201 1 246933929 246940630 6701 het loss 3125 2201 1 246933929 246940630 6701 het loss 3152 2201 1 246933929 246940630 6701 het loss 3173 2201 1 246933929 246940630 6701 het loss 3175 2201 1 246933929 246940630 6701 het loss 3188 2201 1 246933929 246940630 6701 het loss 3193 2201 1 246933929 246940630 6701 het loss 3202 2201 1 246933929 246940630 6701 het loss 3203 2201 1 246933929 246940630 6701 het loss 3205 2201 1 246933929 246940630 6701 hom loss 3163 2201 1 246933929 246940630 6701 hom loss 3273 2201 3 116140997 116146946 5949 het loss 3009 ZBTB20 2202 3 116140997 116146946 5949 het loss 3144 ZBTB20 2202 3 116140997 116146946 5949 het loss 3152 ZBTB20 2202 3 116140997 116146946 5949 het loss 3154 ZBTB20 2202 3 116140997 116146946 5949 het loss 3159 ZBTB20 2202 3 116140997 116146946 5949 het loss 3192 ZBTB20 2202 3 116140997 116146946 5949 het loss 3194 ZBTB20 2202 3 116140997 116146946 5949 het loss 3200 ZBTB20 2202 3 116140997 116146946 5949 het loss 3273 ZBTB20 2202 3 116140997 116146946 5949 hom loss 3173 ZBTB20 2202 14 65143023 65145120 2097 het loss 3006 FUT8 2203 14 65143023 65145120 2097 het loss 3010 FUT8 2203 14 65143023 65145120 2097 het loss 3160 FUT8 2203 14 65143023 65145120 2097 het loss 3178 FUT8 2203 14 65143023 65145120 2097 het loss 3183 FUT8 2203 14 65143023 65145120 2097 het loss 3189 FUT8 2203 14 65143023 65145120 2097 het loss 3194 FUT8 2203 14 65143023 65145120 2097 het loss 3201 FUT8 2203 Table 28A lists recurrent CNVs of interest in this study.

TABLE 28B SRN 364-366, three recurrent CNVs with values of OR >= 3 and FET <= 0.05 (SRN = original CNV since these are recurrent CNVs) CNV Sub- CNV Sub- PML Ref-Seq Exon CNV Sub- region region CNV Sub- CNV Case Gene Over- NVE PML region No. Chr Start Stop region Size Type ID Symbol lap Cases Cases FET OR (SRN) 1 246933929 246940630 6701 het loss 3009 N 5 10 2.02E−09 32.62 364 1 246933929 246940630 6701 het loss 3125 N 5 10 2.02E−09 32.62 364 1 246933929 246940630 6701 het loss 3152 N 5 10 2.02E−09 32.62 364 1 246933929 246940630 6701 het loss 3173 N 5 10 2.02E−09 32.62 364 1 246933929 246940630 6701 het loss 3175 N 5 10 2.02E−09 32.62 364 1 246933929 246940630 6701 het loss 3188 N 5 10 2.02E−09 32.62 364 1 246933929 246940630 6701 het loss 3193 N 5 10 2.02E−09 32.62 364 1 246933929 246940630 6701 het loss 3202 N 5 10 2.02E−09 32.62 364 1 246933929 246940630 6701 het loss 3203 N 5 10 2.02E−09 32.62 364 1 246933929 246940630 6701 het loss 3205 N 5 10 2.02E−09 32.62 364 1 246933929 246940630 6701 hom loss 3163 N 0 2 0.004453 71.98 364 1 246933929 246940630 6701 hom loss 3273 N 0 2 0.004453 71.98 364 3 116140997 116146946 5949 het loss 3009 ZBTB20 N 23 9 0.000122 6.17 365 3 116140997 116146946 5949 het loss 3144 ZBTB20 N 23 9 0.000122 6.17 365 3 116140997 116146946 5949 het loss 3152 ZBTB20 N 23 9 0.000122 6.17 365 3 116140997 116146946 5949 het loss 3154 ZBTB20 N 23 9 0.000122 6.17 365 3 116140997 116146946 5949 het loss 3159 ZBTB20 N 23 9 0.000122 6.17 365 3 116140997 116146946 5949 het loss 3192 ZBTB20 N 23 9 0.000122 6.17 365 3 116140997 116146946 5949 het loss 3194 ZBTB20 N 23 9 0.000122 6.17 365 3 116140997 116146946 5949 het loss 3200 ZBTB20 N 23 9 0.000122 6.17 365 3 116140997 116146946 5949 het loss 3273 ZBTB20 N 23 9 0.000122 6.17 365 3 116140997 116146946 5949 hom loss 3173 ZBTB20 N 0 1 0.004453 42.57 365 14 65143023 65145120 2097 het loss 3006 FUT8 N 34 8 0.004761 3.61 366 14 65143023 65145120 2097 het loss 3010 FUT8 N 34 8 0.004761 3.61 366 14 65143023 65145120 2097 het loss 3160 FUT8 N 34 8 0.004761 3.61 366 14 65143023 65145120 2097 het loss 3178 FUT8 N 34 8 0.004761 3.61 366 14 65143023 65145120 2097 het loss 3183 FUT8 N 34 8 0.004761 3.61 366 14 65143023 65145120 2097 het loss 3189 FUT8 N 34 8 0.004761 3.61 366 14 65143023 65145120 2097 het loss 3194 FUT8 N 34 8 0.004761 3.61 366 14 65143023 65145120 2097 het loss 3201 FUT8 N 34 8 0.004761 3.61 366 Table 28B lists CNVs/CNV subregions of interest with OR and FET values.

TABLE 29 GN 491 and 492, NCBI Gene ID, descriptions, RefSeq summary for 2 of 3 Table 28A genes RefSeq Gene Gene Exon NCBI No. Symbol Overlap Gene ID Gene Description RefSeq Summary (GN) FUT8 intronic 2530 alpha-(1,6)- This gene encodes an enzyme belonging to 491 fucosyltransferase the family of fucosyltransferases. The isoform a product of this gene catalyzes the transfer of fucose from GDP-fucose to N-linked type complex glycopeptides. This enzyme is distinct from other fucosyltransferases which catalyze alpha1-2, alpha1-3, and alpha1-4 fucose addition. The expression of this gene may contribute to the malignancy of cancer cells and to their invasive and metastatic capabilities. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2011]. Transcript Variant: This variant (1, also known as B6) represents the longest transcript and encodes the longer isoform (a). Variants 1 and 3 encode the same isoform. Sequence Note: This RefSeq record was created from transcript and genomic sequence data to make the sequence consistent with the reference genome assembly. The genomic coordinates used for the transcript record were based on transcript alignments. Publication Note: This RefSeq record includes a subset of the publications that are available for this gene. Please see the Gene record to access additional publications. Transcript exon combination:: AJ536056.1, AJ536054.1 [ECO: 0000332] RNAseq introns::single sample supports all introns ERS025084, ERS025088 [ECO: 0000348] ZBTB20 intronic 26137 zinc finger and N/A 492 BTB domain- containing protein 20 isoform 1 Table 29 lists gene information for genes in Table 28B

TABLE 30 SEQ ID 2204-2215, transcript variants for Table 29 genes (FUT8 and ZBTB20, third CNV is intergenic) RefSeq RefSeq Gene Exon Accession SEQ Symbol Overlap Number mRNA Description ID FUT8 intronic NM 004480 Homo sapiens fucosyltransferase 8 (alpha (1,6) 2204 fucosyltransferase) (FUT8), transcript variant 4, mRNA. FUT8 intronic NM 178155 Homo sapiens fucosyltransferase 8 (alpha (1,6) 2205 fucosyltransferase) (FUT8), transcript variant 1, mRNA. FUT8 intronic NM 178156 Homo sapiens fucosyltransferase 8 (alpha (1,6) 2206 fucosyltransferase) (FUT8), transcript variant 3, mRNA. FUT8 intronic NR 038167 Homo sapiens fucosyltransferase 8 (alpha (1,6) 2207 fucosyltransferase) (FUT8), transcript variant 5, non- coding RNA. FUT8 intronic NR 038170 Homo sapiens fucosyltransferase 8 (alpha (1,6) 2208 fucosyltransferase) (FUT8), transcript variant 2, non- coding RNA. ZBTB20 intronic NM 001164343 Homo sapiens zinc finger and BTB domain 2209 containing 20 (ZBTB20), transcript variant 3, mRNA. ZBTB20 intronic NM 015642 Homo sapiens zinc finger and BTB domain containing 2210 20 (ZBTB20), transcript variant 2, mRNA. ZBTB20 intronic NM 001164342 Homo sapiens zinc finger and BTB domain containing 2211 20 (ZBTB20), transcript variant 1, mRNA. ZBTB20 intronic NM 001164347 Homo sapiens zinc finger and BTB domain containing 2212 20 (ZBTB20), transcript variant 7, mRNA. ZBTB20 intronic NM 001164346 Homo sapiens zinc finger and BTB domain containing 2213 20 (ZBTB20), transcript variant 6, mRNA. ZBTB20 intronic NM 001164344 Homo sapiens zinc finger and BTB domain containing 2214 20 (ZBTB20), transcript variant 4, mRNA. ZBTB20 intronic NM 001164345 Homo sapiens zinc finger and BTB domain containing 2215 20 (ZBTB20), transcript variant 5, mRNA. Table 30 represents a non-redundant list of transcript variants that correspond to the Table 29 genes

TABLE 31 GN 493-762, 270 candidate PML genes, updated list from various public databases (e.g., PubMed) RefSeq Gene Disease Gene Number Symbol Model Gene Source Source Annotation (GN) ACD AD AR Public db PMID: 25205116, 25233904, 26810774 493 ACTB AD Public db PMID: 29226301, 29226302 494 ACTN4 AD Public db PMID: 29921932 495 ADA2 AR Public db PMID: 29226301, 29226302, 29867916 496 ADAM17 AR Public db PMID: 29226301, 29226302 497 ADGRL2 unknown Public db PMID: 29921932 498 AIRE AD AR Public db PMID: 29226301,29226302, 29867916 499 ANP32B unknown Public db PMID: 29867916 500 AP1S3 AR Public db PMID: 29226301, 29226302 501 ARPC1B AR Public db PMID: 29226301, 29226302 502 ATG12 unknown Public db PMID: 28141795, 28295214 503 ATG16L1 association Public db PMID: 28141795 504 ATG5 AR Public db PMID: 28141795, 28295214 505 ATG7 unknown Public db PMID: 28141795 506 ATG9A unknown Public db PMID: 28768533, 29360040, 29669830, 507 29928688 ATP6AP1 XLR Public db PMID: 29226301, 29226302 508 B2M AR Public db PMID: 27381292, 29226301, 29226302 509 BCL11B AD Public db PMID: 29226301, 29226302 510 BCL2 association Public db PMID: 29867916 511 BLK AD Public db PMID: 29867916, 29921932 512 BRD4 unknown Public db PMID: 27007123, 29475942 513 BTLA unknown Public db PMID: 29867916 514 C1R AR Public db PMID: 29226301, 29226302, 22773339 515 C1S AR Public db PMID: 29226301, 29226302, 22773339 516 C2 AR Public db PMID: 29226301, 29226302, 22773339 517 C3 AD AR Public db PMID: 29226301, 29226302, 22773339 518 C4A AR Public db PMID: 29226301, 29226302, 22773339 519 C4B AR Public db PMID: 29226301, 29226302, 22773339 520 C5 AR Public db PMID: 29226301, 29226302, 22773339 521 C6 AR Public db PMID: 29226301, 29226302, 22773339 522 C7 AR Public db PMID: 29226301, 29226302, 22773339 523 C8A AR Public db PMID: 29226301, 29226302, 22773339 524 C8B AR Public db PMID: 29226301, 29226302, 22773339 525 C8G AR Public db PMID: 29226301, 29226302, 22773339 526 C9 AR Public db PMID: 29226301, 29226302, 22773339 527 CAD AR Public db PMID: 29921932 528 CAMLG unknown Public db PMID: 29921932 529 CARD14 AD Public db PMID: 29226301, 29226302 530 CASP10 AD Public db PMID: 29226301, 29226302 531 CAV1 AD Public db PMID: 24531836, 25339669, 28805811, 532 29541038, 29674451 CCBE1 AR Public db PMID: 29226301, 29226302 533 CCDC22 XLR Public db PMID: 29921932 534 CCZ1 unknown Public db PMID: 28768533, 29360040, 29669830, 535 29928688 CD22 unknown Public db PMID: 29867916 536 CD274 unknown Public db PMID: 29867916 537 CD276 unknown Public db PMID: 29867916 538 CD36 AR Public db PMID: 29921932 539 CD37 unknown Public db PMID: 29867916 540 CD38 unknown Public db PMID: 29867916 541 CD46 AD Public db PMID: 29226301, 29226302, 22773339 542 CD5 unknown Public db PMID: 29867916 543 CD70 AR Public db PMID: 29226301, 29226302 544 CD72 unknown Public db PMID: 29867916 545 CD74 unknown Public db PMID: 29867916 546 CD84 unknown Public db PMID: 29867916 547 CD93 unknown Public db PMID: 29867916, 22773339 548 CEBPE AR Public db PMID: 27042682, 29226301, 29226302 549 CFB AD AR Public db PMID: 29226301, 29226302, 22773339 550 CFD AR Public db PMID: 29226301, 29226302, 22773339 551 CFH AD AR Public db PMID: 29226301, 29226302, 22773339 552 CFHR1 AD AR Public db PMID: 29226301, 29226302, 22773339 553 CFHR2 AD AR Public db PMID: 29226301, 29226302, 22773339 554 CFHR3 AD AR Public db PMID: 29226301, 29226302, 22773339 555 CFHR4 AD AR Public db PMID: 29226301, 29226302, 22773339 556 CFHR5 AD AR Public db PMID: 29226301, 29226302, 22773339 557 CFI AD AR Public db PMID: 29226301, 29226302, 22773339 558 CFP XLR Public db PMID: 29226301, 29226302, 22773339 559 CFTR AR Public db PMID: 29226301, 29226302 560 CHD2 AD Public db PMID: 29921932 561 CLEC16A unknown Public db PMID: 29867916, 29921932 562 CLPB AR Public db PMID: 29226301, 29226302 563 COPA AD Public db PMID: 29226301, 29226302 564 CSF2RA XLR Public db PMID: 29226301, 29226302 565 CSF2RB AR Public db PMID: 29226301, 29226302 566 CTC1 AR Public db PMID: 29226301, 29226302 567 CXCL1 unknown Public db PMID: 28681388 568 CXCL10 unknown Public db PMID: 23086711, 28237728 569 CXCL5 unknown Public db PMID: 28681388 570 CXCL8 unknown Public db PMID: 28681388 571 CXCR3 unknown Public db PMID: 28237728 572 CYBA AR Public db PMID: 29226301, 29226302 573 DCLRE1B AR Public db PMID: 29226301, 29226302 574 DNAJC21 AR Public db PMID: 29226301, 29226302 575 DNASE1L3 AR Public db PMID: 29226301, 29226302 576 DNASE2 unknown Public db PMID: 29226301, 29226302 577 EBF1 unknown Public db PMID: 29921932 578 EGF association Public db PMID: 29921932 579 ERCC6L2 AR Public db PMID: 29226301, 29226302 580 EXTL3 AR Public db PMID: 29226301, 29226302 581 FAAP24 AR Public db PMID: 29226301, 29226302 582 FADD AR Public db PMID: 29226301, 29226302 583 FAT4 AR Public db PMID: 29226301, 29226302 584 FCER2 unknown Public db PMID: 29867916 585 FERMT3 AR Public db PMID: 29226301, 29226302 586 FIS1 unknown Public db PMID: 28768533, 29360040, 29669830, 587 29928688 G6PD XLD Public db PMID: 29226301, 29226302 588 GINS1 AR Public db PMID: 29226301, 29226302 589 HERC5 unknown Public db PMID: 27381292, 28768533, 29360040, 590 29669830, 29928688 HERC6 unknown Public db PMID: 28768533, 29360040, 29669830, 591 29928688 HMGB1 unknown Public db PMID: 24531836, 25339669, 28805811, 592 29541038, 29674451 HMOX1 AR Public db PMID: 29226301, 29226302 593 HYOU1 AR Public db PMID: 29226301, 29226302 594 ICAM1 association Public db PMID: 29921932 595 ICOSLG unknown Public db PMID: 29867916 596 IFI35 unknown Public db PMID: 27381292, 28236279 597 IFIT1 unknown Public db PMID: 28236279, 28768533, 29360040, 598 29669830, 29928688 IFIT2 unknown Public db PMID: 27381292, 28236279, 28768533, 599 29360040, 29669830, 29921932, 29928688 IFIT3 unknown Public db PMID: 27381292, 28236279, 28768533, 600 29360040, 29669830, 29928688 IGHM AR Public db PMID: 29226301, 29226302, 29867916 601 IGHMBP2 AR Public db PMID: 1714899, 9034313, 11889755, 602 28202949, 29272405 IGKC AR Public db PMID: 29226301, 29226302, 29867916 603 IL17RC AR Public db PMID: 29226301, 29226302 604 IL1RN AR Public db PMID: 29226301, 29226302 605 IL3 unknown Public db PMID: 29867916 606 IL36RN AR Public db PMID: 29226301, 29226302 607 IL4 unknown Public db PMID: 29867916 608 INO80 AR Public db PMID: 29226301, 29226302 609 INPP5D unknown Public db PMID: 29921932 610 IRAK1 XLR Public db PMID: 29226301, 29226302 611 IRF2BP2 AD Public db PMID: 29226301,29226302, 29867916 612 ITCH AR Public db PMID: 28295214, 29226301, 29226302, 613 29867916 ITGAM association Public db PMID: 29921932, 22773339 614 ITGB2 AR Public db PMID: 29226301, 29226302, 22773339 615 ITPKB unknown Public db PMID: 29921932 616 ITSN1 unknown Public db PMID: 29337666, 29599122, 29851086, 617 29958948 JAK1 AD AR Public db PMID: 27648547, 29226301, 29226302 618 KDM6A XLD XLR Public db PMID: 29226301, 29226302 619 KMT2D AD Public db PMID: 29226301, 29226302 620 KRAS AD Public db PMID: 29921932 621 LAT AR Public db PMID: 29226301, 29226302 622 LPINT2 AR Public db PMID: 29226301, 29226302 623 LRRK2 unknown Public db PMID: 26844546, 27830463, 28202666, 624 28768533, 29321258, 29360040, 29499195, 29669830, 29755459, 29760073, 29850629 MAP3K14 AR Public db PMID: 29226301, 29226302 625 MASP2 AR Public db PMID: 29226301, 29226302, 22773339 626 MB21D1 unknown Public db PMID: 27648547 627 MBL2 AD Public db PMID: 29867916, 22773339 628 MCM4 AR Public db PMID: 29226301, 29226302 629 MCM5 AR Public db PMID: 29921932 630 MDC1 unknown Public db PMID: 29921932 631 MEF2C AD Public db PMID: 29921932 632 MEFV AD AR Public db PMID: 29226301, 29226302 633 MFN1 unknown Public db PMID: 28768533, 29360040, 29669830, 634 29928688 MFN2 AD AR Public db PMID: 28768533, 29360040, 29669830, 635 29928688 MLH1 AD AR Public db PMID: 29867916, 29921932 636 MMP9 association Public db PMID: 28681388 637 MOGS AR Public db PMID: 29226301, 29226302 638 MON1A unknown Public db PMID: 28768533, 29360040, 29669830, 639 29928688 MON1B unknown Public db PMID: 28768533, 29360040, 29669830, 640 29928688 MSH2 AD AR Public db PMID: 29867916, 29921932 641 MSH5 AR Public db PMID: 29867916, 29921932 642 MSH6 AR Public db PMID: 29226301, 29226302 643 MVK AD AR Public db PMID: 29226301, 29226302 644 MX1 unknown Public db PMID: 27381292, 28236279 645 MX2 unknown Public db PMID: 27381292, 28236279 646 MYSM1 AR Public db PMID: 29226301, 29226302 647 NBAS AR Public db PMID: 29226301, 29226302 648 NCF1 AR Public db PMID: 29226301, 29226302 649 NCF2 AR Public db PMID: 29226301, 29226302 650 NCF4 AR Public db PMID: 29226301, 29226302 651 NCSTN AD Public db PMID: 29226301, 29226302 652 NFAT5 AD Public db PMID: 29226301, 29226302 653 NHP2 AR Public db PMID: 29226301, 29226302 654 NLRC4 AD Public db PMID: 29226301, 29226302 655 NLRP1 AR Public db PMID: 29226301, 29226302 656 NLRP2 unknown Public db PMID: 29921932 657 NLRX1 unknown Public db PMID: 28295214 658 NOD1 unknown Public db PMID: 29921932 659 NOP10 AR Public db PMID: 29226301, 29226302 660 NSMCE3 AR Public db PMID: 29226301, 29226302 661 OAS1 AR Public db PMID: 27381292, 28236279 662 OAS2 unknown Public db PMID: 27381292, 28236279 663 OAS3 unknown Public db PMID: 27381292, 28236279 664 OASL unknown Public db PMID: 27381292, 28236279 665 ORC4 AR Public db PMID: 29867916, 29921932 666 OTULIN AR Public db PMID: 29226301, 29226302 667 PARN AD AR Public db PMID: 26810774, 29226301, 29226302 668 PCCA AR Public db PMID: 29921932 669 PCCB AR Public db PMID: 29921932 670 PDCD1 association Public db PMID: 29867916 671 PDCD1LG2 unknown Public db PMID: 29867916 672 PEPD AR Public db PMID: 29226301, 29226302 673 PINK1 AR Public db PMID: 28768533, 29360040, 29669830, 674 29928688 PLAU AD Public db PMID: 28681388 675 PLAUR unknown Public db PMID: 28681388 676 PLCG1 unknown Public db PMID: 29921932 677 PLD1 AR Public db PMID: 29921932 678 PLEKHM1 AR Public db PMID: 29226301, 29226302 679 PLK1 unknown Public db PMID: 28295214 680 PLXNB1 unknown Public db PMID: 29921932 681 PMM2 AR Public db PMID: 19862844, 24474243, 27415628 682 POLE2 AR Public db PMID: 29226301, 29226302 683 PPM1A unknown Public db PMID: 28295214 684 PRKN AR Public db PMID: 28768533, 29360040, 29669830, 685 29928688 PRRC2A unknown Public db PMID: 29921932 686 PSEN1 AD Public db PMID: 29226301, 29226302 687 PSENEN AD Public db PMID: 29226301, 29226302 688 PSMA7 unknown Public db PMID: 28295214 689 RAB5A unknown Public db PMID: 28768533, 29360040, 29669830, 690 29928688 RAB5B unknown Public db PMID: 28768533, 29360040, 29669830, 691 29928688 RAB5C unknown Public db PMID: 28768533, 29360040, 29669830, 692 29928688 RAD50 association Public db PMID: 29867916, 29921932 693 RANBP2 AD Public db PMID: 29226301, 29226302 694 RASGRP1 AR Public db PMID: 29226301, 29226302 695 RELA unknown Public db PMID: 27042682, 27648547 696 RELB AR Public db PMID: 29226301, 29226302 697 RHOH AR Public db PMID: 29226301, 29226302 698 RLTPR AR Public db PMID: 29226301, 29226302 699 RNF125 AD Public db PMID: 28295214 700 RORC AR Public db PMID: 29226301, 29226302 701 RPSA AD Public db PMID: 29226301, 29226302 702 RSAD2 unknown Public db PMID: 27381292, 28236279, 28768533, 703 29360040, 29669830, 29928688 SAMD9 AD Public db PMID: 29226301, 29226302 704 SAMD9L AD Public db PMID: 29226301, 29226302 705 SEMA3E AD Public db PMID: 29226301, 29226302 706 SERPINA1 AR Public db PMID: 29867916 707 SERPINB2 unknown Public db PMID: 28681388 708 SERPING1 AD Public db PMID: 29226301, 29226302, 22773339 709 SH3BP2 AD Public db PMID: 29226301, 29226302 710 SLC29A3 AR Public db PMID: 29226301, 29226302 711 SLC35C1 AR Public db PMID: 29226301, 29226302 712 SLC7A7 AR Public db PMID: 10655553, 20301535 713 SLC9A1 AR Public db PMID: 29921932 714 SMARCAL1 AR Public db PMID: 29226301, 29226302 715 SMARCD2 AR Public db PMID: 29226301, 29226302 716 SMC3 AD Public db PMID: 29921932 717 SMURF2 unknown Public db PMID: 28295214 718 SRP54 unknown Public db PMID: 29226301, 29226302 719 STN1 AR Public db PMID: 29226301, 29226302 720 TBC1D15 unknown Public db PMID: 28768533, 29360040, 29669830, 721 29928688 TBC1D17 unknown Public db PMID: 28768533, 29360040, 29669830, 722 29928688 TCF3 AD Public db PMID: 29226301, 29226302 723 TCN2 AR Public db PMID: 29226301, 29226302 724 TEK AD Public db PMID: 29921932 725 TERC AD Public db PMID: 29226301, 29226302 726 TERT AD AR Public db PMID: 26810774, 29226301, 29226302 727 TFPI unknown Public db PMID: 28681388 728 TFRC AR Public db PMID: 29226301, 29226302 729 THBD AD Public db PMID: 28681388, 29226301, 29226302 730 THBS1 unknown Public db PMID: 29921932 731 TINF2 AD Public db PMID: 26810774, 29226301, 29226302 732 TIRAP AR Public db PMID: 29226301, 29226302 733 TMC6 AR Public db PMID: 29226301, 29226302 734 TMC8 AR Public db PMID: 29226301, 29226302 735 TNFRSF17 unknown Public db PMID: 29867916 736 TNFRSF1A AD Public db PMID: 29226301, 29226302 737 TNFSF10 unknown Public db PMID: 29867916 738 TNFSF13 unknown Public db PMID: 29867916 739 TNFSF13B unknown Public db PMID: 29867916 740 TNIP1 unknown Public db PMID: 29921932 741 TP53AIP1 unknown Public db PMID: 29921932 742 TPP1 AD AR Public db PMID: 29226301, 29226302 743 TPP2 AR Public db PMID: 29226301, 29226302 744 TRAC AR Public db PMID: 29226301, 29226302 745 TRAF3IP2 AR Public db PMID: 29226301, 29226302 746 TRIM25 unknown Public db PMID: 28295214 747 TRIM37 AR Public db PMID: 29921932 748 TTC37 AR Public db PMID: 29226301, 29226302 749 UBD unknown Public db PMID: 28295214 750 USB1 AR Public db PMID: 29226301, 29226302 751 USP15 unknown Public db PMID: 28295214 752 USP21 unknown Public db PMID: 28295214 753 USP25 unknown Public db PMID: 28295214 754 USP3 unknown Public db PMID: 28295214 755 VAV1 unknown Public db PMID: 29867916, 29921932 756 VDR AD AR Public db PMID: 29867916 757 VEGFA association Public db PMID: 28681388 758 WASHC5 AD AR Public db PMID: 29921932 759 WDR1 AR Public db PMID: 29226301, 29226302 760 WRAP53 AR Public db PMID: 29226301, 29226302 761 XAF1 unknown Public db PMID: 27381292, 28236279 762 Table 31 represents a non-redundant list of 270 genes involved in the immune system that are not listed in Table 6.

TABLE 32 SEQ ID 2300-2893, transcript variants for Table 31 genes RefSeq Gene RefSeq Accession Symbol Number mRNA Description SEQ ID ACD NM 001082486 Homo sapiens adrenocortical dysplasia homolog (mouse) 2300 (ACD), transcript variant 1, mRNA. ACD NM 001082487 Homo sapiens adrenocortical dysplasia homolog (mouse) 2301 (ACD), transcript variant 3, mRNA. ACD NM 022914 Homo sapiens adrenocortical dysplasia homolog (mouse) 2302 (ACD), transcript variant 2, mRNA. ACTB NM 001101 Homo sapiens actin, beta (ACTB), mRNA. 2303 ACTN4 NM 004924 Homo sapiens actinin, alpha 4 (ACTN4), mRNA. 2304 ADA2 NM 001282225.1 Homo sapiens adenosine deaminase 2, transcript variant 3 2305 ADA2 NM 001282226.1 Homo sapiens adenosine deaminase 2, transcript variant 4 2306 ADA2 NM 001282227.1 Homo sapiens adenosine deaminase 2, transcript variant 5 2307 ADA2 NM 001282228.1 Homo sapiens adenosine deaminase 2, transcript variant 6 2308 ADA2 NM 001282229.1 Homo sapiens adenosine deaminase 2, transcript variant 7 2309 ADA2 NM 177405.2 Homo sapiens adenosine deaminase 2, transcript variant 2 2310 ADAM17 NM 003183 Homo sapiens ADAM metallopeptidase domain 17 2311 (ADAM17), mRNA. ADGRL2 NM 001297704.2 Homo sapiens adhesion G protein-coupled receptor L2, 2312 transcript variant 2 ADGRL2 NM 001297705.2 Homo sapiens adhesion G protein-coupled receptor L2, 2313 transcript variant 3 ADGRL2 NM 001297706.2 Homo sapiens adhesion G protein-coupled receptor L2, 2314 transcript variant 4 ADGRL2 NM 001330645.2 Homo sapiens adhesion G protein-coupled receptor L2, 2315 transcript variant 5 ADGRL2 NM 001350698.1 Homo sapiens adhesion G protein-coupled receptor L2, 2316 transcript variant 6 ADGRL2 NM 001350699.1 Homo sapiens adhesion G protein-coupled receptor L2, 2317 transcript variant 7 ADGRL2 NM 012302.4 Homo sapiens adhesion G protein-coupled receptor L2, 2318 transcript variant 1 AIRE NM 000383 Homo sapiens autoimmune regulator (AIRE), mRNA. 2319 ANP32B NM 006401 Homo sapiens acidic (leucine-rich) nuclear phosphoprotein 2320 32 family, member B (ANP32B), mRNA. AP1S3 NM 001039569 Homo sapiens adaptor-related protein complex 1, sigma 3 2321 subunit (AP1S3), mRNA. ARPC1B NM 005720 Homo sapiens actin related protein ⅔ complex, subunit 1B, 2322 41 kDa (ARPC1B), mRNA. ATG12 NM 004707 Homo sapiens autophagy related 12 (ATG12), transcript 2323 variant 1, mRNA. ATG12 NR 033362 Homo sapiens autophagy related 12 (ATG12), transcript 2324 variant 2, non-coding RNA. ATG12 NR 033363 Homo sapiens autophagy related 12 (ATG12), transcript 2325 variant 3, non-coding RNA. ATG12 NR 073603 Homo sapiens autophagy related 12 (ATG12), transcript 2326 variant 4, non-coding RNA. ATG12 NR 073604 Homo sapiens autophagy related 12 (ATG12), transcript 2327 variant 5, non-coding RNA. ATG12 NR 073605 Homo sapiens autophagy related 12 (ATG12), transcript 2328 variant 5, non-coding RNA. ATG16L1 NM 001190266 Homo sapiens autophagy related 16-like 1 (S. cerevisiae) 2329 (ATG16L1), transcript variant 4, mRNA. ATG16L1 NM 001190267 Homo sapiens autophagy related 16-like 1 (S. cerevisiae) 2330 (ATG16L1), transcript variant 5, mRNA. ATG16L1 NM 017974 Homo sapiens autophagy related 16-like 1 (S. cerevisiae) 2331 (ATG16L1), transcript variant 2, mRNA. ATG16L1 NM 030803 Homo sapiens autophagy related 16-like 1 (S. cerevisiae) 2332 (ATG16L1), transcript variant 1, mRNA. ATG16L1 NM 198890 Homo sapiens autophagy related 16-like 1 (S. cerevisiae) 2333 (ATG16L1), transcript variant 3, mRNA. ATG5 NM 004849 Homo sapiens autophagy related 5 (ATG5), mRNA. 2334 ATG7 NM 001136031 Homo sapiens autophagy related 7 (ATG7), transcript 2335 variant 2, mRNA. ATG7 NM 001144912 Homo sapiens autophagy related 7 (ATG7), transcript 2336 variant 3, mRNA. ATG7 NM 006395 Homo sapiens autophagy related 7 (ATG7), transcript 2337 variant 1, mRNA. ATG9A NM 001077198 Homo sapiens autophagy related 9A (ATG9A), transcript 2338 variant 1, mRNA. ATG9A NM 024085 Homo sapiens autophagy related 9A (ATG9A), transcript 2339 variant 2, mRNA. ATP6AP1 NM 001183 Homo sapiens ATPase, H+ transporting, lysosomal 2340 accessory protein 1 (ATP6AP1), mRNA. B2M NM 004048 Homo sapiens beta-2-microglobulin (B2M), mRNA. 2341 BCL11B NM 022898 Homo sapiens B-cell CLL/lymphoma 11B (zinc finger 2342 protein) (BCL11B), transcript variant 2, mRNA. BCL11B NM 138576 Homo sapiens B-cell CLL/lymphoma 11B (zinc finger 2343 protein) (BCL11B), transcript variant 1, mRNA. BCL2 NM 000633 Homo sapiens B-cell CLL/lymphoma 2 (BCL2), transcript 2344 variant alpha, mRNA. BCL2 NM 000657 Homo sapiens B-cell CLL/lymphoma 2 (BCL2), transcript 2345 variant beta, mRNA. BLK NM 001715 Homo sapiens B lymphoid tyrosine kinase (BLK), mRNA. 2346 BRD4 NM 014299 Homo sapiens bromodomain containing 4 (BRD4), 2347 transcript variant short, mRNA. BRD4 NM 058243 Homo sapiens bromodomain containing 4 (BRD4), 2348 transcript variant long, mRNA. BTLA NM 001085357 Homo sapiens B and T lymphocyte associated (BTLA), 2349 transcript variant 2, mRNA. BTLA NM 181780 Homo sapiens B and T lymphocyte associated (BTLA), 2350 transcript variant 1, mRNA. C1R NM 001733 Homo sapiens complement component 1, r subcomponent 2351 (C1R), mRNA. C1S NM 001734 Homo sapiens complement component 1, s subcomponent 2352 (C1S), transcript variant 2, mRNA. C1S NM 201442 Homo sapiens complement component 1, s subcomponent 2353 (C1S), transcript variant 1, mRNA. C2 NM 000063 Homo sapiens complement component 2 (C2), transcript 2354 variant 1, mRNA. C2 NM 001145903 Homo sapiens complement component 2 (C2), transcript 2355 variant 2, mRNA. C2 NM 001178063 Homo sapiens complement component 2 (C2), transcript 2356 variant 3, mRNA. C2 NR 073063 Homo sapiens complement component 2 (C2), transcript 2357 variant 4, non-coding RNA. C3 NM 000064 Homo sapiens complement component 3 (C3), mRNA. 2358 C4A NM 001252204 Homo sapiens complement component 4A (Rodgers blood 2359 group) (C4A), transcript variant 2, mRNA. C4A NM 007293 Homo sapiens complement component 4A (Rodgers blood 2360 group) (C4A), transcript variant 1, mRNA. C4B NM 001002029 Homo sapiens complement component 4B (Chido blood 2361 group) (C4B), mRNA. C5 NM 001735 Homo sapiens complement component 5 (C5), mRNA. 2362 C6 NM 000065 Homo sapiens complement component 6 (C6), transcript 2363 variant 1, mRNA. C6 NM 001115131 Homo sapiens complement component 6 (C6), transcript 2364 variant 2, mRNA. C7 NM 000587 Homo sapiens complement component 7 (C7), mRNA. 2365 C8A NM 000562 Homo sapiens complement component 8, alpha polypeptide 2366 (C8A), mRNA. C8B NM 000066 Homo sapiens complement component 8, beta polypeptide 2367 (C8B), transcript variant 1, mRNA. C8G NM 000606 Homo sapiens complement component 8, gamma 2368 polypeptide (C8G), mRNA. C9 NM 001737 Homo sapiens complement component 9 (C9), mRNA. 2369 CAD NM 004341 Homo sapiens carbamoyl-phosphate synthetase 2, aspartate 2370 transcarbamylase, and dihydroorotase (CAD), mRNA. CAMLG NM 001745 Homo sapiens calcium modulating ligand (CAMLG), 2371 mRNA. CARD14 NM 001257970 Homo sapiens caspase recruitment domain family, member 2372 14 (CARD14), transcript variant 3, mRNA. CARD14 NM 024110 Homo sapiens caspase recruitment domain family, member 2373 14 (CARD14), transcript variant 1, mRNA. CARD14 NM 052819 Homo sapiens caspase recruitment domain family, member 2374 14 (CARD14), transcript variant 2, mRNA. CARD14 NR 047566 Homo sapiens caspase recruitment domain family, member 2375 14 (CARD14), transcript variant 4, non-coding RNA. CASP10 NM 001206524 Homo sapiens caspase 10, apoptosis-related cysteine 2376 peptidase (CASP10), transcript variant 6, mRNA. CASP10 NM 001206542 Homo sapiens caspase 10, apoptosis-related cysteine 2377 peptidase (CASP10), transcript variant 5, mRNA. CASP10 NM 001230 Homo sapiens caspase 10, apoptosis-related cysteine 2378 peptidase (CASP10), transcript variant 3, mRNA. CASP10 NM 032974 Homo sapiens caspase 10, apoptosis-related cysteine 2379 peptidase (CASP10), transcript variant 2, mRNA. CASP10 NM 032976 Homo sapiens caspase 10, apoptosis-related cysteine 2380 peptidase (CASP10), transcript variant 4, mRNA. CASP10 NM 032977 Homo sapiens caspase 10, apoptosis-related cysteine 2381 peptidase (CASP10), transcript variant 1, mRNA. CAV1 NM 001172895 Homo sapiens caveolin 1, caveolae protein, 22 kDa (CAV1), 2382 transcript variant 2, mRNA. CAV1 NM 001172896 Homo sapiens caveolin 1, caveolae protein, 22 kDa (CAV1), 2383 transcript variant 3, mRNA. CAV1 NM 001172897 Homo sapiens caveolin 1, caveolae protein, 22 kDa (CAV1), 2384 transcript variant 4, mRNA. CAV1 NM 001753 Homo sapiens caveolin 1, caveolae protein, 22 kDa (CAV1), 2385 transcript variant 1, mRNA. CCBE1 NM 133459 Homo sapiens collagen and calcium binding EGF domains 1 2386 (CCBE1), mRNA. CCDC22 NM 014008 Homo sapiens coiled-coil domain containing 22 (CCDC22), 2387 mRNA. CCZ1 NM 015622 Homo sapiens CCZ1 vacuolar protein trafficking and 2388 biogenesis associated homolog (S. cerevisiae) (CCZ1), mRNA. CD22 NM 001185099 Homo sapiens CD22 molecule (CD22), transcript variant 2, 2389 mRNA. CD22 NM 001185100 Homo sapiens CD22 molecule (CD22), transcript variant 3, 2390 mRNA. CD22 NM 001185101 Homo sapiens CD22 molecule (CD22), transcript variant 4, 2391 mRNA. CD22 NM 001771 Homo sapiens CD22 molecule (CD22), transcript variant 1, 2392 mRNA. CD274 NM 001267706 Homo sapiens CD274 molecule (CD274), transcript variant 2393 2, mRNA. CD274 NM 014143 Homo sapiens CD274 molecule (CD274), transcript variant 2394 1, mRNA. CD274 NR 052005 Homo sapiens CD274 molecule (CD274), transcript variant 2395 3, non-coding RNA. CD276 NM 001024736 Homo sapiens CD276 molecule (CD276), transcript variant 2396 1, mRNA. CD276 NM 025240 Homo sapiens CD276 molecule (CD276), transcript variant 2397 2, mRNA. CD36 NM 000072 Homo sapiens CD36 molecule (thrombospondin receptor) 2398 (CD36), transcript variant 3, mRNA. CD36 NM 001001547 Homo sapiens CD36 molecule (thrombospondin receptor) 2399 (CD36), transcript variant 2, mRNA. CD36 NM 001001548 Homo sapiens CD36 molecule (thrombospondin receptor) 2400 (CD36), transcript variant 1, mRNA. CD36 NM 001127443 Homo sapiens CD36 molecule (thrombospondin receptor) 2401 (CD36), transcript variant 4, mRNA. CD36 NM 001127444 Homo sapiens CD36 molecule (thrombospondin receptor) 2402 (CD36), transcript variant 5, mRNA. CD37 NM 001040031 Homo sapiens CD37 molecule (CD37), transcript variant 2, 2403 mRNA. CD37 NM 001774 Homo sapiens CD37 molecule (CD37), transcript variant 1, 2404 mRNA. CD38 NM 001775 Homo sapiens CD38 molecule (CD38), mRNA. 2405 CD46 NM 002389 Homo sapiens CD46 molecule, complement regulatory 2406 protein (CD46), transcript variant a, mRNA. CD46 NM 153826 Homo sapiens CD46 molecule, complement regulatory 2407 protein (CD46), transcript variant d, mRNA. CD46 NM 172350 Homo sapiens CD46 molecule, complement regulatory 2408 protein (CD46), transcript variant n, mRNA. CD46 NM 172351 Homo sapiens CD46 molecule, complement regulatory 2409 protein (CD46), transcript variant c, mRNA. CD46 NM 172352 Homo sapiens CD46 molecule, complement regulatory 2410 protein (CD46), transcript variant e, mRNA. CD46 NM 172353 Homo sapiens CD46 molecule, complement regulatory 2411 protein (CD46), transcript variant f, mRNA. CD46 NM 172359 Homo sapiens CD46 molecule, complement regulatory 2412 protein (CD46), transcript variant b, mRNA. CD46 NM 172361 Homo sapiens CD46 molecule, complement regulatory 2413 protein (CD46), transcript variant l, mRNA. CD5 NM 014207 Homo sapiens CD5 molecule (CD5), mRNA. 2414 CD70 NM 001252 Homo sapiens CD70 molecule (CD70), mRNA. 2415 CD72 NM 001782 Homo sapiens CD72 molecule (CD72), mRNA. 2416 CD74 NM 001025158 Homo sapiens CD74 molecule, major histocompatibility 2417 complex, class II invariant chain (CD74), transcript variant 3, mRNA. CD74 NM 001025159 Homo sapiens CD74 molecule, major histocompatibility 2418 complex, class II invariant chain (CD74), transcript variant 1, mRNA. CD74 NM 004355 Homo sapiens CD74 molecule, major histocompatibility 2419 complex, class II invariant chain (CD74), transcript variant 2, mRNA. CD84 NM 001184879 Homo sapiens CD84 molecule (CD84), transcript variant 1, 2420 mRNA. CD84 NM 001184881 Homo sapiens CD84 molecule (CD84), transcript variant 3, 2421 mRNA. CD84 NM 001184882 Homo sapiens CD84 molecule (CD84), transcript variant 4, 2422 mRNA. CD84 NM 003874 Homo sapiens CD84 molecule (CD84), transcript variant 2, 2423 mRNA. CD93 NM 012072 Homo sapiens CD93 molecule (CD93), mRNA. 2424 CEBPE NM 001805 Homo sapiens CCAAT/enhancer binding protein (C/EBP), 2425 epsilon (CEBPE), mRNA. CFB NM 001710 Homo sapiens complement factor B (CFB), mRNA. 2426 CFD NM 001928 Homo sapiens complement factor D (adipsin) (CFD), 2427 mRNA. CFH NM 000186 Homo sapiens complement factor H (CFH), transcript 2428 variant 1, mRNA. CFH NM 001014975 Homo sapiens complement factor H (CFH), transcript 2429 variant 2, mRNA. CFHR1 NM 002113 Homo sapiens complement factor H-related 1 (CFHR1), 2430 mRNA. CFHR2 NM 005666 Homo sapiens complement factor H-related 2 (CFHR2), 2431 mRNA. CFHR3 NM 001166624 Homo sapiens complement factor H-related 3 (CFHR3), 2432 transcript variant 2, mRNA. CFHR3 NM 021023 Homo sapiens complement factor H-related 3 (CFHR3), 2433 transcript variant 1, mRNA. CFHR4 NM 001201550 Homo sapiens complement factor H-related 4 (CFHR4), 2434 transcript variant 1, mRNA. CFHR4 NM 001201551 Homo sapiens complement factor H-related 4 (CFHR4), 2435 transcript variant 2, mRNA. CFHR4 NM 006684 Homo sapiens complement factor H-related 4 (CFHR4), 2436 transcript variant 3, mRNA. CFHR5 NM 030787 Homo sapiens complement factor H-related 5 (CFHR5), 2437 mRNA. CFI NM 000204 Homo sapiens complement factor I (CFI), mRNA. 2438 CFP NM 001145252 Homo sapiens complement factor properdin (CFP), 2439 transcript variant 2, mRNA. CFP NM 002621 Homo sapiens complement factor properdin (CFP), 2440 transcript variant 1, mRNA. CFTR NM 000492 Homo sapiens cystic fibrosis transmembrane conductance 2441 regulator (ATP-binding cassette sub-family C, member 7) (CFTR), mRNA. CHD2 NM 001042572 Homo sapiens chromodomain helicase DNA binding protein 2442 2 (CHD2), transcript variant 2, mRNA. CHD2 NM 001271 Homo sapiens chromodomain helicase DNA binding protein 2443 2 (CHD2), transcript variant 1, mRNA. CLEC16A NM 001243403 Homo sapiens C-type lectin domain family 16, member A 2444 (CLEC16A), transcript variant 2, mRNA. CLEC16A NM 015226 Homo sapiens C-type lectin domain family 16, member A 2445 (CLEC16A), transcript variant 1, mRNA. CLPB NM 001258392 Homo sapiens ClpB caseinolytic peptidase B homolog (E. 2446 coli) (CLPB), transcript variant 2, mRNA. CLPB NM 001258393 Homo sapiens ClpB caseinolytic peptidase B homolog (E. 2447 coli) (CLPB), transcript variant 3, mRNA. CLPB NM 001258394 Homo sapiens ClpB caseinolytic peptidase B homolog (E. 2448 coli) (CLPB), transcript variant 4, mRNA. CLPB NM 030813 Homo sapiens ClpB caseinolytic peptidase B homolog (E. 2449 coli) (CLPB), transcript variant 1, mRNA. COPA NM 001098398 Homo sapiens coatomer protein complex, subunit alpha 2450 (COPA), transcript variant 1, mRNA. COPA NM 004371 Homo sapiens coatomer protein complex, subunit alpha 2451 (COPA), transcript variant 2, mRNA. CSF2RA NM 001161529 Homo sapiens colony stimulating factor 2 receptor, alpha, 2452 low-affinity (granulocyte-macrophage) (CSF2RA), transcript variant 7, mRNA. CSF2RA NM 001161530 Homo sapiens colony stimulating factor 2 receptor, alpha, 2453 low-affinity (granulocyte-macrophage) (CSF2RA), transcript variant 8, mRNA. CSF2RA NM 001161531 Homo sapiens colony stimulating factor 2 receptor, alpha, 2454 low-affinity (granulocyte-macrophage) (CSF2RA), transcript variant 9, mRNA. CSF2RA NM 001161532 Homo sapiens colony stimulating factor 2 receptor, alpha, 2455 low-affinity (granulocyte-macrophage) (CSF2RA), transcript variant 10, mRNA. CSF2RA NM 006140 Homo sapiens colony stimulating factor 2 receptor, alpha, 2456 low-affinity (granulocyte-macrophage) (CSF2RA), transcript variant 1, mRNA. CSF2RA NM 172245 Homo sapiens colony stimulating factor 2 receptor, alpha, 2457 low-affinity (granulocyte-macrophage) (CSF2RA), transcript variant 2, mRNA. CSF2RA NM 172246 Homo sapiens colony stimulating factor 2 receptor, alpha, 2458 low-affinity (granulocyte-macrophage) (CSF2RA), transcript variant 3, mRNA. CSF2RA NM 172247 Homo sapiens colony stimulating factor 2 receptor, alpha, 2459 low-affinity (granulocyte-macrophage) (CSF2RA), transcript variant 4, mRNA. CSF2RA NM 172249 Homo sapiens colony stimulating factor 2 receptor, alpha, 2460 low-affinity (granulocyte-macrophage) (CSF2RA), transcript variant 6, mRNA. CSF2RA NR 027760 Homo sapiens colony stimulating factor 2 receptor, alpha, 2461 low-affinity (granulocyte-macrophage) (CSF2RA), transcript variant 11, non-coding RNA. CSF2RB NM 000395 Homo sapiens colony stimulating factor 2 receptor, beta, 2462 low-affinity (granulocyte-macrophage) (CSF2RB), mRNA. CTC1 NM 025099 Homo sapiens CTS telomere maintenance complex 2463 component 1 (CTC1), transcript variant 1, mRNA. CTC1 NR 046431 Homo sapiens CTS telomere maintenance complex 2464 component 1 (CTC1), transcript variant 2, non-coding RNA. CXCL1 NM 001511 Homo sapiens chemokine (C-X-C motif) ligand 1 2465 (melanoma growth stimulating activity, alpha) (CXCL1), transcript variant 1, mRNA. CXCL1 NR 046035 Homo sapiens chemokine (C-X-C motif) ligand 1 2466 (melanoma growth stimulating activity, alpha) (CXCL1), transcript variant 2, non-coding RNA. CXCL10 NM 001565 Homo sapiens chemokine (C-X-C motif) ligand 10 2467 (CXCL10), mRNA. CXCL5 NM 002994 Homo sapiens chemokine (C-X-C motif) ligand 5 (CXCL5), 2468 mRNA. CXCL8 NM 000584.3 Homo sapiens C-X-C motif chemokine ligand 8, transcript 2469 variant 1 CXCL8 NM 001354840.1 Homo sapiens C-X-C motif chemokine ligand 8, transcript 2470 variant 2 CXCR3 NM 001142797 Homo sapiens chemokine (C-X-C motif) receptor 3 2471 (CXCR3), transcript variant 2, mRNA. CXCR3 NM 001504 Homo sapiens chemokine (C-X-C motif) receptor 3 2472 (CXCR3), transcript variant 1, mRNA. CYBA NM 000101 Homo sapiens cytochrome b-245, alpha polypeptide 2473 (CYBA), mRNA. DCLRE1B NM 022836 Homo sapiens DNA cross-link repair 1B (DCLRE1B), 2474 mRNA. DNAJC21 NM 001012339 Homo sapiens DnaJ (Hsp40) homolog, subfamily C, 2475 member 21 (DNAJC21), transcript variant 2, mRNA. DNAJC21 NM 194283 Homo sapiens DnaJ (Hsp40) homolog, subfamily C, 2476 member 21 (DNAJC21), transcript variant 1, mRNA. DNASE1L3 NM 001256560 Homo sapiens deoxyribonuclease I-like 3 (DNASE1L3), 2477 transcript variant 2, mRNA. DNASE1L3 NM 004944 Homo sapiens deoxyribonuclease I-like 3 (DNASE1L3), 2478 transcript variant 1, mRNA. DNASE2 NM 001375 Homo sapiens deoxyribonuclease II, lysosomal (DNASE2), 2479 mRNA. EBF1 NM 024007 Homo sapiens early B-cell factor 1 (EBF1), mRNA. 2480 EGF NM 001178130 Homo sapiens epidermal growth factor (EGF), transcript 2481 variant 2, mRNA. EGF NM 001178131 Homo sapiens epidermal growth factor (EGF), transcript 2482 variant 3, mRNA. EGF NM 001963 Homo sapiens epidermal growth factor (EGF), transcript 2483 variant 1, mRNA. ERCC6L2 NM 001010895 Homo sapiens excision repair cross-complementing rodent 2484 repair deficiency, complementation group 6-like 2 (ERCC6L2), mRNA. EXTL3 NM 001440 Homo sapiens exostosin-like glycosyltransferase 3 2485 (EXTL3), transcript variant 1, mRNA. EXTL3 NR 073468 Homo sapiens exostosin-like glycosyltransferase 3 2486 (EXTL3), transcript variant 2, non-coding RNA. EXTL3 NR 073469 Homo sapiens exostosin-like glycosyltransferase 3 2487 (EXTL3), transcript variant 3, non-coding RNA. FAAP24 NM 001300978.1 Homo sapiens Fanconi anemia core complex associated 2488 protein 24, transcript variant 2 FAAP24 NM 152266.4 Homo sapiens Fanconi anemia core complex associated 2489 protein 24, transcript variant 1 FADD NM 003824 Homo sapiens Fas (TNFRSF6)-associated via death domain 2490 (FADD), mRNA. FAT4 NM 024582 Homo sapiens FAT atypical cadherin 4 (FAT4), mRNA. 2491 FCER2 NM 001207019 Homo sapiens Fc fragment of IgE, low affinity II, receptor 2492 for (CD23) (FCER2), transcript variant 2, mRNA. FCER2 NM 001220500 Homo sapiens Fc fragment of IgE, low affinity II, receptor 2493 for (CD23) (FCER2), transcript variant 3, mRNA. FCER2 NM 002002 Homo sapiens Fc fragment of IgE, low affinity II, receptor 2494 for (CD23) (FCER2), transcript variant 1, mRNA. FERMT3 NM 031471 Homo sapiens fermitin family member 3 (FERMT3), 2495 transcript variant URP2SF, mRNA. FERMT3 NM 178443 Homo sapiens fermitin family member 3 (FERMT3), 2496 transcript variant URP2LF, mRNA. FIS1 NM 016068 Homo sapiens fission 1 (mitochondrial outer membrane) 2497 homolog (S. cerevisiae) (FIS1), mRNA. G6PD NM 000402 Homo sapiens glucose-6-phosphate dehydrogenase (G6PD), 2498 transcript variant 1, mRNA. G6PD NM 001042351 Homo sapiens glucose-6-phosphate dehydrogenase (G6PD), 2499 transcript variant 2, mRNA. GINS1 NM 021067 Homo sapiens GINS complex subunit 1 (Psf1 homolog) 2500 (GINS1), mRNA. HERC5 NM 016323 Homo sapiens HECT and RLD domain containing E3 2501 ubiquitin protein ligase 5 (HERC5), mRNA. HERC6 NM 001165136 Homo sapiens HECT and RLD domain containing E3 2502 ubiquitin protein ligase family member 6 (HERC6), transcript variant 2, mRNA. HERC6 NM 017912 Homo sapiens HECT and RLD domain containing E3 2503 ubiquitin protein ligase family member 6 (HERC6), transcript variant 1, mRNA. HMGB1 NM 002128 Homo sapiens high mobility group box 1 (HMGB1), 2504 mRNA. HMOX1 NM 002133 Homo sapiens heme oxygenase (decycling) 1 (HMOX1), 2505 mRNA. HYOU1 NM 001130991 Homo sapiens hypoxia up-regulated 1 (HYOU1), transcript 2506 variant 2, mRNA. HYOU1 NM 006389 Homo sapiens hypoxia up-regulated 1 (HYOU1), transcript 2507 variant 1, mRNA. ICAM1 NM 000201 Homo sapiens intercellular adhesion molecule 1 (ICAM1), 2508 mRNA. ICOSLG NM 015259 Homo sapiens inducible T-cell co-stimulator ligand 2509 (ICOSLG), mRNA. IFI35 NM 005533 Homo sapiens interferon-induced protein 35 (IFI35), 2510 mRNA. IFIT1 NM 001270927 Homo sapiens interferon-induced protein with 2511 tetratricopeptide repeats 1 (IFIT1), transcript variant 2, mRNA. IFIT1 NM 001270928 Homo sapiens interferon-induced protein with 2512 tetratricopeptide repeats 1 (IFIT1), transcript variant 3, mRNA. IFIT1 NM 001270929 Homo sapiens interferon-induced protein with 2513 tetratricopeptide repeats 1 (IFIT1), transcript variant 4, mRNA. IFIT1 NM 001270930 Homo sapiens interferon-induced protein with 2514 tetratricopeptide repeats 1 (IFIT1), transcript variant 5, mRNA. IFIT1 NM 001548 Homo sapiens interferon-induced protein with 2515 tetratricopeptide repeats 1 (IFIT1), transcript variant 1, mRNA. IFIT2 NM 001547 Homo sapiens interferon-induced protein with 2516 tetratricopeptide repeats 2 (IFIT2), mRNA. IFIT3 NM 001031683 Homo sapiens interferon-induced protein with 2517 tetratricopeptide repeats 3 (IFIT3), transcript variant 2, mRNA. IFIT3 NM 001549 Homo sapiens interferon-induced protein with 2518 tetratricopeptide repeats 3 (IFIT3), transcript variant 1, mRNA. IGHMBP2 NM 002180 Homo sapiens immunoglobulin mu binding protein 2 2519 (IGHMBP2), mRNA. IL17RC NM 001203263 Homo sapiens interleukin 17 receptor C (IL17RC), transcript 2520 variant 4, mRNA. IL17RC NM 001203264 Homo sapiens interleukin 17 receptor C (IL17RC), transcript 2521 variant 5, mRNA. IL17RC NM 001203265 Homo sapiens interleukin 17 receptor C (IL17RC), transcript 2522 variant 6, mRNA. IL17RC NM 032732 Homo sapiens interleukin 17 receptor C (IL17RC), transcript 2523 variant 3, mRNA. IL17RC NM 153460 Homo sapiens interleukin 17 receptor C (IL17RC), transcript 2524 variant 1, mRNA. IL17RC NM 153461 Homo sapiens interleukin 17 receptor C (IL17RC), transcript 2525 variant 2, mRNA. IL17RC NR 037807 Homo sapiens interleukin 17 receptor C (IL17RC), transcript 2526 variant 7, non-coding RNA. IL1RN NM 000577 Homo sapiens interleukin 1 receptor antagonist (IL1RN), 2527 transcript variant 3, mRNA. IL1RN NM 173841 Homo sapiens interleukin 1 receptor antagonist (IL1RN), 2528 transcript variant 2, mRNA. IL1RN NM 173842 Homo sapiens interleukin 1 receptor antagonist (IL1RN), 2529 transcript variant 1, mRNA. IL1RN NM 173843 Homo sapiens interleukin 1 receptor antagonist (IL1RN), 2530 transcript variant 4, mRNA. IL3 NM 000588 Homo sapiens interleukin 3 (colony-stimulating factor, 2531 multiple) (IL3), mRNA. IL36RN NM 012275 Homo sapiens interleukin 36 receptor antagonist (IL36RN), 2532 transcript variant 1, mRNA. IL36RN NM 173170 Homo sapiens interleukin 36 receptor antagonist (IL36RN), 2533 transcript variant 2, mRNA. IL4 NM 000589 Homo sapiens interleukin 4 (IL4), transcript variant 1, 2534 mRNA. IL4 NM 172348 Homo sapiens interleukin 4 (IL4), transcript variant 2, 2535 mRNA. INO80 NM 017553 Homo sapiens INO80 complex subunit (INO80), transcript 2536 variant 1, mRNA. INPP5D NM 001017915 Homo sapiens inositol polyphosphate-5-phosphatase, 2537 145 kDa (INPP5D), transcript variant 1, mRNA. INPP5D NM 005541 Homo sapiens inositol polyphosphate-5-phosphatase, 2538 145 kDa (INPP5D), transcript variant 2, mRNA. IRAK1 NM 001025242 Homo sapiens interleukin-1 receptor-associated kinase 1 2539 (IRAK1), transcript variant 2, mRNA. IRAK1 NM 001025243 Homo sapiens interleukin-1 receptor-associated kinase 1 2540 (IRAK1), transcript variant 3, mRNA. IRAK1 NM 001569 Homo sapiens interleukin-1 receptor-associated kinase 1 2541 (IRAK1), transcript variant 1, mRNA. IRF2BP2 NM 001077397 Homo sapiens interferon regulatory factor 2 binding protein 2542 2 (IRF2BP2), transcript variant 2, mRNA. IRF2BP2 NM 182972 Homo sapiens interferon regulatory factor 2 binding protein 2543 2 (IRF2BP2), transcript variant 1, mRNA. ITCH NM 001257137 Homo sapiens itchy E3 ubiquitin protein ligase (ITCH), 2544 transcript variant 1, mRNA. ITCH NM 001257138 Homo sapiens itchy E3 ubiquitin protein ligase (ITCH), 2545 transcript variant 3, mRNA. ITCH NM 031483 Homo sapiens itchy E3 ubiquitin protein ligase (ITCH), 2546 transcript variant 2, mRNA. ITGAM NM 000632 Homo sapiens integrin, alpha M (complement component 3 2547 receptor 3 subunit) (ITGAM), transcript variant 2, mRNA. ITGAM NM 001145808 Homo sapiens integrin, alpha M (complement component 3 2548 receptor 3 subunit) (ITGAM), transcript variant 1, mRNA. ITGB2 NM 000211 Homo sapiens integrin, beta 2 (complement component 3 2549 receptor 3 and 4 subunit) (ITGB2), transcript variant 1, mRNA. ITGB2 NM 001127491 Homo sapiens integrin, beta 2 (complement component 3 2550 receptor 3 and 4 subunit) (ITGB2), transcript variant 2, mRNA. ITPKB NM 002221 Homo sapiens inositol-trisphosphate 3-kinase B (ITPKB), 2551 mRNA. ITSN1 NM 001001132 Homo sapiens intersectin 1 (SH3 domain protein) (ITSN1), 2552 transcript variant 2, mRNA. ITSN1 NM 003024 Homo sapiens intersectin 1 (SH3 domain protein) (ITSN1), 2553 transcript variant 1, mRNA. JAK1 NM 002227 Homo sapiens Janus kinase 1 (JAK1), mRNA. 2554 KDM6A NM 021140 Homo sapiens lysine (K)-specific demethylase 6A 2555 (KDM6A), mRNA. KMT2D NM 003482 Homo sapiens lysine (K)-specific methyltransferase 2D 2556 (KMT2D), mRNA. KRAS NM 004985 Homo sapiens Kirsten rat sarcoma viral oncogene homolog 2557 (KRAS), transcript variant b, mRNA. KRAS NM 033360 Homo sapiens Kirsten rat sarcoma viral oncogene homolog 2558 (KRAS), transcript variant a, mRNA. LAT NM 001014987 Homo sapiens linker for activation of T cells (LAT), 2559 transcript variant 2, mRNA. LAT NM 001014988 Homo sapiens linker for activation of T cells (LAT), 2560 transcript variant 3, mRNA. LAT NM 001014989 Homo sapiens linker for activation of T cells (LAT), 2561 transcript variant 4, mRNA. LAT NM 014387 Homo sapiens linker for activation of T cells (LAT), 2562 transcript variant 1, mRNA. LPIN2 NM 014646 Homo sapiens lipin 2 (LPIN2), mRNA. 2563 LRRK2 NM 198578 Homo sapiens leucine-rich repeat kinase 2 (LRRK2), 2564 mRNA. MAP3K14 NM 003954 Homo sapiens mitogen-activated protein kinase kinase 2565 kinase 14 (MAP3K14), mRNA. MASP2 NM 006610 Homo sapiens mannan-binding lectin serine peptidase 2 2566 (MASP2), transcript variant 1, mRNA. MASP2 NM 139208 Homo sapiens mannan-binding lectin serine peptidase 2 2567 (MASP2), transcript variant 2, mRNA. MB21D1 NM 138441 Homo sapiens Mab-21 domain containing 1 (MB21D1), 2568 mRNA. MBL2 NM 000242 Homo sapiens mannose-binding lectin (protein C) 2, soluble 2569 (MBL2), mRNA. MCM4 NM 005914 Homo sapiens minichromosome maintenance complex 2570 component 4 (MCM4), transcript variant 1, mRNA. MCM4 NM 182746 Homo sapiens minichromosome maintenance complex 2571 component 4 (MCM4), transcript variant 2, mRNA. MCM5 NM 006739 Homo sapiens minichromosome maintenance complex 2572 component 5 (MCM5), mRNA. MDC1 NM 014641 Homo sapiens mediator of DNA-damage checkpoint 1 2573 (MDC1), mRNA. MEF2C NM 001131005 Homo sapiens myocyte enhancer factor 2C (MEF2C), 2574 transcript variant 2, mRNA. MEF2C NM 001193347 Homo sapiens myocyte enhancer factor 2C (MEF2C), 2575 transcript variant 3, mRNA. MEF2C NM 001193348 Homo sapiens myocyte enhancer factor 2C (MEF2C), 2576 transcript variant 4, mRNA. MEF2C NM 001193349 Homo sapiens myocyte enhancer factor 2C (MEF2C), 2577 transcript variant 5, mRNA. MEF2C NM 001193350 Homo sapiens myocyte enhancer factor 2C (MEF2C), 2578 transcript variant 6, mRNA. MEF2C NM 002397 Homo sapiens myocyte enhancer factor 2C (MEF2C), 2579 transcript variant 1, mRNA. MEFV NM 000243 Homo sapiens Mediterranean fever (MEFV), transcript 2580 variant 1, mRNA. MEFV NM 001198536 Homo sapiens Mediterranean fever (MEFV), transcript 2581 variant 2, mRNA. MFN1 NM 033540 Homo sapiens mitofusin 1 (MFN1), mRNA. 2582 MFN2 NM 001127660 Homo sapiens mitofusin 2 (MFN2), transcript variant 2, 2583 mRNA. MFN2 NM 014874 Homo sapiens mitofusin 2 (MFN2), transcript variant 1, 2584 mRNA. MLH1 NM 000249 Homo sapiens mutL homolog 1, colon cancer, nonpolyposis 2585 type 2 (E. coli) (MLH1), transcript variant 1, mRNA. MLH1 NM 001167617 Homo sapiens mutL homolog 1, colon cancer, nonpolyposis 2586 type 2 (E. coli) (MLH1), transcript variant 2, mRNA. MLH1 NM 001167618 Homo sapiens mutL homolog 1, colon cancer, nonpolyposis 2587 type 2 (E. coli) (MLH1), transcript variant 3, mRNA. MLH1 NM 001167619 Homo sapiens mutL homolog 1, colon cancer, nonpolyposis 2588 type 2 (E. coli) (MLH1), transcript variant 4, mRNA. MLH1 NM 001258271 Homo sapiens mutL homolog 1, colon cancer, nonpolyposis 2589 type 2 (E. coli) (MLH1), transcript variant 5, mRNA. MLH1 NM 001258273 Homo sapiens mutL homolog 1, colon cancer, nonpolyposis 2590 type 2 (E. coli) (MLH1), transcript variant 6, mRNA. MLH1 NM 001258274 Homo sapiens mutL homolog 1, colon cancer, nonpolyposis 2591 type 2 (E. coli) (MLH1), transcript variant 7, mRNA. MMP9 NM 004994 Homo sapiens matrix metallopeptidase 9 (gelatinase B, 2592 92 kDa gelatinase, 92 kDa type IV collagenase) (MMP9), mRNA. MOGS NM 001146158 Homo sapiens mannosyl-oligosaccharide glucosidase 2593 (MOGS), transcript variant 2, mRNA. MOGS NM 006302 Homo sapiens mannosyl-oligosaccharide glucosidase 2594 (MOGS), transcript variant 1, mRNA. MON1A NM 001142501 Homo sapiens MON1 secretory trafficking family member 2595 A (MON1A), transcript variant 2, mRNA. MON1A NM 032355 Homo sapiens MON1 secretory trafficking family member 2596 A (MON1A), transcript variant 1, mRNA. MON1B NM 014940 Homo sapiens MON1 secretory trafficking family member 2597 B (MON1B), mRNA. MSH2 NM 000251 Homo sapiens mutS homolog 2, colon cancer, nonpolyposis 2598 type 1 (E. coli) (MSH2), transcript variant 1, mRNA. MSH2 NM 001258281 Homo sapiens mutS homolog 2, colon cancer, nonpolyposis 2599 type 1 (E. coli) (MSH2), transcript variant 2, mRNA. MSH5 NM 002441 Homo sapiens mutS homolog 5 (E. coli) (MSH5), transcript 2600 variant 3, mRNA. MSH5 NM 025259 Homo sapiens mutS homolog 5 (E. coli) (MSH5), transcript 2601 variant 1, mRNA. MSH5 NM 172165 Homo sapiens mutS homolog 5 (E. coli) (MSH5), transcript 2602 variant 2, mRNA. MSH5 NM 172166 Homo sapiens mutS homolog 5 (E. coli) (MSH5), transcript 2603 variant 4, mRNA. MSH6 NM 000179 Homo sapiens mutS homolog 6 (E. coli) (MSH6), transcript 2604 variant 1, mRNA. MVK NM 000431 Homo sapiens mevalonate kinase (MVK), transcript variant 2605 1, mRNA. MVK NM 001114185 Homo sapiens mevalonate kinase (MVK), transcript variant 2606 2, mRNA. MX1 NM 001144925 Homo sapiens myxovirus (influenza virus) resistance 1, 2607 interferon-inducible protein p78 (mouse) (MX1), transcript variant 1, mRNA. MX1 NM 001178046 Homo sapiens myxovirus (influenza virus) resistance 1, 2608 interferon-inducible protein p78 (mouse) (MX1), transcript variant 3, mRNA. MX1 NM 002462 Homo sapiens myxovirus (influenza virus) resistance 1, 2609 interferon-inducible protein p78 (mouse) (MX1), transcript variant 2, mRNA. MX2 NM 002463 Homo sapiens myxovirus (influenza virus) resistance 2 2610 (mouse) (MX2), mRNA. MYSM1 NM 001085487 Homo sapiens Myb-like, SWIRM and MPN domains 1 2611 (MYSM1), mRNA. NBAS NM 015909 Homo sapiens neuroblastoma amplified sequence (NBAS), 2612 transcript variant 1, mRNA. NBAS NR 052013 Homo sapiens neuroblastoma amplified sequence (NBAS), 2613 transcript variant 2, non-coding RNA. NCF1 NM 000265 Homo sapiens neutrophil cytosolic factor 1 (NCF1), mRNA. 2614 NCF2 NM 000433 Homo sapiens neutrophil cytosolic factor 2 (NCF2), 2615 transcript variant 1, mRNA. NCF2 NM 001127651 Homo sapiens neutrophil cytosolic factor 2 (NCF2), 2616 transcript variant 2, mRNA. NCF2 NM 001190789 Homo sapiens neutrophil cytosolic factor 2 (NCF2), 2617 transcript variant 4, mRNA. NCF2 NM 001190794 Homo sapiens neutrophil cytosolic factor 2 (NCF2), 2618 transcript variant 3, mRNA. NCF4 NM 000631 Homo sapiens neutrophil cytosolic factor 4, 40 kDa (NCF4), 2619 transcript variant 1, mRNA. NCF4 NM 013416 Homo sapiens neutrophil cytosolic factor 4, 40 kDa (NCF4), 2620 transcript variant 2, mRNA. NCSTN NM 015331 Homo sapiens nicastrin (NCSTN), mRNA. 2621 NFAT5 NM 001113178 Homo sapiens nuclear factor of activated T-cells 5, tonicity- 2622 responsive (NFAT5), transcript variant 6, mRNA. NFAT5 NM 006599 Homo sapiens nuclear factor of activated T-cells 5, tonicity- 2623 responsive (NFAT5), transcript variant 3, mRNA. NFAT5 NM 138713 Homo sapiens nuclear factor of activated T-cells 5, tonicity- 2624 responsive (NFAT5), transcript variant 2, mRNA. NFAT5 NM 138714 Homo sapiens nuclear factor of activated T-cells 5, tonicity- 2625 responsive (NFAT5), transcript variant 1, mRNA. NFAT5 NM 173214 Homo sapiens nuclear factor of activated T-cells 5, tonicity- 2626 responsive (NFAT5), transcript variant 4, mRNA. NFAT5 NM 173215 Homo sapiens nuclear factor of activated T-cells 5, tonicity- 2627 responsive (NFAT5), transcript variant 5, mRNA. NHP2 NM 001034833 Homo sapiens NHP2 ribonucleoprotein (NHP2), transcript 2628 variant 2, mRNA. NHP2 NM 017838 Homo sapiens NHP2 ribonucleoprotein (NHP2), transcript 2629 variant 1, mRNA. NLRC4 NM 001199138 Homo sapiens NLR family, CARD domain containing 4 2630 (NLRC4), transcript variant 2, mRNA. NLRC4 NM 001199139 Homo sapiens NLR family, CARD domain containing 4 2631 (NLRC4), transcript variant 3, mRNA. NLRC4 NM 021209 Homo sapiens NLR family, CARD domain containing 4 2632 (NLRC4), transcript variant 1, mRNA. NLRP1 NM 001033053 Homo sapiens NLR family, pyrin domain containing 1 2633 (NLRP1), transcript variant 5, mRNA. NLRP1 NM 014922 Homo sapiens NLR family, pyrin domain containing 1 2634 (NLRP1), transcript variant 2, mRNA. NLRP1 NM 033004 Homo sapiens NLR family, pyrin domain containing 1 2635 (NLRP1), transcript variant 1, mRNA. NLRP1 NM 033006 Homo sapiens NLR family, pyrin domain containing 1 2636 (NLRP1), transcript variant 3, mRNA. NLRP1 NM 033007 Homo sapiens NLR family, pyrin domain containing 1 2637 (NLRP1), transcript variant 4, mRNA. NLRP2 NM 001174081 Homo sapiens NLR family, pyrin domain containing 2 2638 (NLRP2), transcript variant 2, mRNA. NLRP2 NM 001174082 Homo sapiens NLR family, pyrin domain containing 2 2639 (NLRP2), transcript variant 3, mRNA. NLRP2 NM 001174083 Homo sapiens NLR family, pyrin domain containing 2 2640 (NLRP2), transcript variant 4, mRNA. NLRP2 NM 017852 Homo sapiens NLR family, pyrin domain containing 2 2641 (NLRP2), transcript variant 1, mRNA. NLRX1 NM 024618 Homo sapiens NLR family member X1 (NLRX1), transcript 2642 variant 1, mRNA. NLRX1 NM 170722 Homo sapiens NLR family member X1 (NLRX1), transcript 2643 variant 2, mRNA. NOD1 NM 006092 Homo sapiens nucleotide-binding oligomerization domain 2644 containing 1 (NOD1), mRNA. NOP10 NM 018648 Homo sapiens NOP10 ribonucleoprotein (NOP10), mRNA. 2645 NSMCE3 NM 138704.3 Homo sapiens NSE3 homolog, SMC5-SMC6 complex 2646 component OAS1 NM 001032409 Homo sapiens 2′-5′-oligoadenylate synthetase 1, 40/46 kDa 2647 (OAS1), transcript variant 3, mRNA. OAS1 NM 002534 Homo sapiens 2′-5′-oligoadenylate synthetase 1, 40/46 kDa 2648 (OAS1), transcript variant 2, mRNA. OAS1 NM 016816 Homo sapiens 2′-5′-oligoadenylate synthetase 1, 40/46 kDa 2649 (OAS1), transcript variant 1, mRNA. OAS2 NM 001032731 Homo sapiens 2′-5′-oligoadenylate synthetase 2, 69/71 kDa 2650 (OAS2), transcript variant 3, mRNA. OAS2 NM 002535 Homo sapiens 2′-5′-oligoadenylate synthetase 2, 69/71 kDa 2651 (OAS2), transcript variant 2, mRNA. OAS2 NM 016817 Homo sapiens 2′-5′-oligoadenylate synthetase 2, 69/71 kDa 2652 (OAS2), transcript variant 1, mRNA. OAS3 NM 006187 Homo sapiens 2′-5′-oligoadenylate synthetase 3, 100 kDa 2653 (OAS3), mRNA. OASL NM 001261825 Homo sapiens 2′-5′-oligoadenylate synthetase-like (OASL), 2654 transcript variant 3, mRNA. OASL NM 003733 Homo sapiens 2′-5′-oligoadenylate synthetase-like (OASL), 2655 transcript variant 1, mRNA. OASL NM 198213 Homo sapiens 2′-5′-oligoadenylate synthetase-like (OASL), 2656 transcript variant 2, mRNA. ORC4 NM 001190879 Homo sapiens origin recognition complex, subunit 4 2657 (ORC4), transcript variant 4, mRNA. ORC4 NM 001190881 Homo sapiens origin recognition complex, subunit 4 2658 (ORC4), transcript variant 5, mRNA. ORC4 NM 001190882 Homo sapiens origin recognition complex, subunit 4 2659 (ORC4), transcript variant 6, mRNA. ORC4 NM 002552 Homo sapiens origin recognition complex, subunit 4 2660 (ORC4), transcript variant 2, mRNA. ORC4 NM 181741 Homo sapiens origin recognition complex, subunit 4 2661 (ORC4), transcript variant 1, mRNA. ORC4 NM 181742 Homo sapiens origin recognition complex, subunit 4 2662 (ORC4), transcript variant 3, mRNA. OTULIN NM 138348.5 Homo sapiens OTU deubiquitinase with linear linkage 2663 specificity PARN NM 001134477 Homo sapiens poly(A)-specific ribonuclease (PARN), 2664 transcript variant 2, mRNA. PARN NM 001242992 Homo sapiens poly(A)-specific ribonuclease (PARN), 2665 transcript variant 3, mRNA. PARN NM 002582 Homo sapiens poly(A)-specific ribonuclease (PARN), 2666 transcript variant 1, mRNA. PCCA NM 000282 Homo sapiens propionyl CoA carboxylase, alpha 2667 polypeptide (PCCA), transcript variant 1, mRNA. PCCA NM 001127692 Homo sapiens propionyl CoA carboxylase, alpha 2668 polypeptide (PCCA), transcript variant 2, mRNA. PCCA NM 001178004 Homo sapiens propionyl CoA carboxylase, alpha 2669 polypeptide (PCCA), transcript variant 3, mRNA. PCCB NM 000532 Homo sapiens propionyl CoA carboxylase, beta polypeptide 2670 (PCCB), transcript variant 1, mRNA. PCCB NM 001178014 Homo sapiens propionyl CoA carboxylase, beta polypeptide 2671 (PCCB), transcript variant 2, mRNA. PDCD1 NM 005018 Homo sapiens programmed cell death 1 (PDCD1), mRNA. 2672 PDCD1LG2 NM 025239 Homo sapiens programmed cell death 1 ligand 2 2673 (PDCD1LG2), mRNA. PEPD NM 000285 Homo sapiens peptidase D (PEPD), transcript variant 1, 2674 mRNA. PEPD NM 001166056 Homo sapiens peptidase D (PEPD), transcript variant 2, 2675 mRNA. PEPD NM 001166057 Homo sapiens peptidase D (PEPD), transcript variant 3, 2676 mRNA. PINK1 NM 032409 Homo sapiens PTEN induced putative kinase 1 (PINK1), 2677 mRNA. PLAU NM 001145031 Homo sapiens plasminogen activator, urokinase (PLAU), 2678 transcript variant 2, mRNA. PLAU NM 002658 Homo sapiens plasminogen activator, urokinase (PLAU), 2679 transcript variant 1, mRNA. PLAUR NM 001005376 Homo sapiens plasminogen activator, urokinase receptor 2680 (PLAUR), transcript variant 2, mRNA. PLAUR NM 001005377 Homo sapiens plasminogen activator, urokinase receptor 2681 (PLAUR), transcript variant 3, mRNA. PLAUR NM 002659 Homo sapiens plasminogen activator, urokinase receptor 2682 (PLAUR), transcript variant 1, mRNA. PLCG1 NM 002660 Homo sapiens phospholipase C, gamma 1 (PLCG1), 2683 transcript variant 1, mRNA. PLCG1 NM 182811 Homo sapiens phospholipase C, gamma 1 (PLCG1), 2684 transcript variant 2, mRNA. PLD1 NM 001130081 Homo sapiens phospholipase D1, phosphatidylcholine- 2685 specific (PLD1), transcript variant 2, mRNA. PLD1 NM 002662 Homo sapiens phospholipase D1, phosphatidylcholine- 2686 specific (PLD1), transcript variant 1, mRNA. PLEKHM1 NM 014798 Homo sapiens pleckstrin homology domain containing, 2687 family M (with RUN domain) member 1 (PLEKHM1), transcript variant 1, mRNA. PLEKHM1 NR 027774 Homo sapiens pleckstrin homology domain containing, 2688 family M (with RUN domain) member 1 (PLEKHM1), transcript variant 2, non-coding RNA. PLEKHM1 NR 027782 Homo sapiens pleckstrin homology domain containing, 2689 family M (with RUN domain) member 1 (PLEKHM1), transcript variant 3, non-coding RNA. PLK1 NM 005030 Homo sapiens polo-like kinase 1 (PLK1), mRNA. 2690 PLXNB1 NM 001130082 Homo sapiens plexin B1 (PLXNB1), transcript variant 2, 2691 mRNA. PLXNB1 NM 002673 Homo sapiens plexin B1 (PLXNB1), transcript variant 1, 2692 mRNA. PMM2 NM 000303 Homo sapiens phosphomannomutase 2 (PMM2), mRNA. 2693 POLE2 NM 001197330 Homo sapiens polymerase (DNA directed), epsilon 2, 2694 accessory subunit (POLE2), transcript variant 2, mRNA. POLE2 NM 001197331 Homo sapiens polymerase (DNA directed), epsilon 2, 2695 accessory subunit (POLE2), transcript variant 3, mRNA. POLE2 NM 002692 Homo sapiens polymerase (DNA directed), epsilon 2, 2696 accessory subunit (POLE2), transcript variant 1, mRNA. PPM1A NM 021003 Homo sapiens protein phosphatase, Mg2+/Mn2+ dependent, 2697 1A (PPM1A), transcript variant 1, mRNA. PPM1A NM 177951 Homo sapiens protein phosphatase, Mg2+/Mn2+ dependent, 2698 1A (PPM1A), transcript variant 2, mRNA. PPM1A NM 177952 Homo sapiens protein phosphatase, Mg2+/Mn2+ dependent, 2699 1A (PPM1A), transcript variant 3, mRNA. PRKN NM 004562.2 Homo sapiens parkin RBR E3 ubiquitin protein ligase, 2700 transcript variant 1 PRKN NM 013987.2 Homo sapiens parkin RBR E3 ubiquitin protein ligase, 2701 transcript variant 2 PRKN NM 013988.2 Homo sapiens parkin RBR E3 ubiquitin protein ligase, 2702 transcript variant 3 PRRC2A NM 004638 Homo sapiens proline-rich coiled-coil 2A (PRRC2A), 2703 transcript variant 2, mRNA. PRRC2A NM 080686 Homo sapiens proline-rich coiled-coil 2A (PRRC2A), 2704 transcript variant 1, mRNA. PSEN1 NM 000021 Homo sapiens presenilin 1 (PSEN1), transcript variant 1, 2705 mRNA. PSEN1 NM 007318 Homo sapiens presenilin 1 (PSEN1), transcript variant 2, 2706 mRNA. PSENEN NM 172341 Homo sapiens presenilin enhancer 2 homolog (C. elegans) 2707 (PSENEN), transcript variant 1, mRNA. PSMA7 NM 002792 Homo sapiens proteasome (prosome, macropain) subunit, 2708 alpha type, 7 (PSMA7), mRNA. RAB5A NM 004162 Homo sapiens RAB5A, member RAS oncogene family 2709 (RAB5A), mRNA. RAB5B NM 001252036 Homo sapiens RAB5B, member RAS oncogene family 2710 (RAB5B), transcript variant 2, mRNA. RAB5B NM 001252037 Homo sapiens RAB5B, member RAS oncogene family 2711 (RAB5B), transcript variant 3, mRNA. RAB5B NM 002868 Homo sapiens RAB5B, member RAS oncogene family 2712 (RAB5B), transcript variant 1, mRNA. RAB5C NM 001252039 Homo sapiens RAB5C, member RAS oncogene family 2713 (RAB5C), transcript variant 3, mRNA. RAB5C NM 004583 Homo sapiens RAB5C, member RAS oncogene family 2714 (RAB5C), transcript variant 2, mRNA. RAB5C NM 201434 Homo sapiens RAB5C, member RAS oncogene family 2715 (RAB5C), transcript variant 1, mRNA. RAD50 NM 005732 Homo sapiens RAD50 homolog (S. cerevisiae) (RAD50), 2716 mRNA. RANBP2 NM 006267 Homo sapiens RAN binding protein 2 (RANBP2), mRNA. 2717 RASGRP1 NM 001128602 Homo sapiens RAS guanyl releasing protein 1 (calcium and 2718 DAG-regulated) (RASGRP1), transcript variant 2, mRNA. RASGRP1 NM 005739 Homo sapiens RAS guanyl releasing protein 1 (calcium and 2719 DAG-regulated) (RASGRP1), transcript variant 1, mRNA. RELA NM 001145138 Homo sapiens v-rel avian reticuloendotheliosis viral 2720 oncogene homolog A (RELA), transcript variant 2, mRNA. RELA NM 001243984 Homo sapiens v-rel avian reticuloendotheliosis viral 2721 oncogene homolog A (RELA), transcript variant 3, mRNA. RELA NM 001243985 Homo sapiens v-rel avian reticuloendotheliosis viral 2722 oncogene homolog A (RELA), transcript variant 4, mRNA. RELA NM 021975 Homo sapiens v-rel avian reticuloendotheliosis viral 2723 oncogene homolog A (RELA), transcript variant 1, mRNA. RELB NM 006509 Homo sapiens v-rel avian reticuloendotheliosis viral 2724 oncogene homolog B (RELB), mRNA. RHOH NM 004310 Homo sapiens ras homolog family member H (RHOH), 2725 transcript variant 6, mRNA. RLTPR NM 001013838 Homo sapiens RGD motif, leucine rich repeats, 2726 tropomodulin domain and proline-rich containing (RLTPR), mRNA. RNF125 NM 017831 Homo sapiens ring finger protein 125, E3 ubiquitin protein 2727 ligase (RNF125), mRNA. RORC NM 001001523 Homo sapiens RAR-related orphan receptor C (RORC), 2728 transcript variant 2, mRNA. RORC NM 005060 Homo sapiens RAR-related orphan receptor C (RORC), 2729 transcript variant 1, mRNA. RPSA NM 001012321 Homo sapiens ribosomal protein SA (RPSA), transcript 2730 variant 2, mRNA. RPSA NM 002295 Homo sapiens ribosomal protein SA (RPSA), transcript 2731 variant 1, mRNA. RSAD2 NM 080657 Homo sapiens radical 5-adenosyl methionine domain 2732 containing 2 (RSAD2), mRNA. SAMD9 NM 001193307 Homo sapiens sterile alpha motif domain containing 9 2733 (SAMD9), transcript variant 2, mRNA. SAMD9 NM 017654 Homo sapiens sterile alpha motif domain containing 9 2734 (SAMD9), transcript variant 1, mRNA. SAMD9L NM 152703 Homo sapiens sterile alpha motif domain containing 9-like 2735 (SAMD9L), mRNA. SEMA3E NM 001178129 Homo sapiens sema domain, immunoglobulin domain (Ig), 2736 short basic domain, secreted, (semaphorin) 3E (SEMA3E), transcript variant 2, mRNA. SEMA3E NM 012431 Homo sapiens sema domain, immunoglobulin domain (Ig), 2737 short basic domain, secreted, (semaphorin) 3E (SEMA3E), transcript variant 1, mRNA. SERPINA1 NM 000295 Homo sapiens serpin peptidase inhibitor, clade A (alpha-1 2738 antiproteinase, antitrypsin), member 1 (SERPINA1), transcript variant 1, mRNA. SERPINA1 NM 001002235 Homo sapiens serpin peptidase inhibitor, clade A (alpha-1 2739 antiproteinase, antitrypsin), member 1 (SERPINA1), transcript variant 3, mRNA. SERPINA1 NM 001002236 Homo sapiens serpin peptidase inhibitor, clade A (alpha-1 2740 antiproteinase, antitrypsin), member 1 (SERPINA1), transcript variant 2, mRNA. SERPINA1 NM 001127700 Homo sapiens serpin peptidase inhibitor, clade A (alpha-1 2741 antiproteinase, antitrypsin), member 1 (SERPINA1), transcript variant 4, mRNA. SERPINA1 NM 001127701 Homo sapiens serpin peptidase inhibitor, clade A (alpha-1 2742 antiproteinase, antitrypsin), member 1 (SERPINA1), transcript variant 5, mRNA. SERPINA1 NM 001127702 Homo sapiens serpin peptidase inhibitor, clade A (alpha-1 2743 antiproteinase, antitrypsin), member 1 (SERPINA1), transcript variant 6, mRNA. SERPINA1 NM 001127703 Homo sapiens serpin peptidase inhibitor, clade A (alpha-1 2744 antiproteinase, antitrypsin), member 1 (SERPINA1), transcript variant 7, mRNA. SERPINA1 NM 001127704 Homo sapiens serpin peptidase inhibitor, clade A (alpha-1 2745 antiproteinase, antitrypsin), member 1 (SERPINA1), transcript variant 8, mRNA. SERPINA1 NM 001127705 Homo sapiens serpin peptidase inhibitor, clade A (alpha-1 2746 antiproteinase, antitrypsin), member 1 (SERPINA1), transcript variant 9, mRNA. SERPINA1 NM 001127706 Homo sapiens serpin peptidase inhibitor, clade A (alpha-1 2747 antiproteinase, antitrypsin), member 1 (SERPINA1), transcript variant 10, mRNA. SERPINA1 NM 001127707 Homo sapiens serpin peptidase inhibitor, clade A (alpha-1 2748 antiproteinase, antitrypsin), member 1 (SERPINA1), transcript variant 11, mRNA. SERPINB2 NM 001143818 Homo sapiens serpin peptidase inhibitor, clade B 2749 (ovalbumin), member 2 (SERPINB2), transcript variant 1, mRNA. SERPINB2 NM 002575 Homo sapiens serpin peptidase inhibitor, clade B 2750 (ovalbumin), member 2 (SERPINB2), transcript variant 2, mRNA. SERPING1 NM 000062 Homo sapiens serpin peptidase inhibitor, clade G (C1 2751 inhibitor), member 1 (SERPING1), transcript variant 1, mRNA. SERPING1 NM 001032295 Homo sapiens serpin peptidase inhibitor, clade G (C1 2752 inhibitor), member 1 (SERPING1), transcript variant 2, mRNA. SH3BP2 NM 001122681 Homo sapiens SH3-domain binding protein 2 (SH3BP2), 2753 transcript variant 2, mRNA. SH3BP2 NM 001145855 Homo sapiens SH3-domain binding protein 2 (SH3BP2), 2754 transcript variant 4, mRNA. SH3BP2 NM 001145856 Homo sapiens SH3-domain binding protein 2 (SH3BP2), 2755 transcript variant 3, mRNA. SH3BP2 NM 003023 Homo sapiens SH3-domain binding protein 2 (SH3BP2), 2756 transcript variant 1, mRNA. SLC29A3 NM 001174098 Homo sapiens solute carrier family 29 (equilibrative 2757 nucleoside transporter), member 3 (SLC29A3), transcript variant 2, mRNA. SLC29A3 NM 018344 Homo sapiens solute carrier family 29 (equilibrative 2758 nucleoside transporter), member 3 (SLC29A3), transcript variant 1, mRNA. SLC29A3 NR 033413 Homo sapiens solute carrier family 29 (equilibrative 2759 nucleoside transporter), member 3 (SLC29A3), transcript variant 3, non-coding RNA. SLC29A3 NR 033414 Homo sapiens solute carrier family 29 (equilibrative 2760 nucleoside transporter), member 3 (SLC29A3), transcript variant 4, non-coding RNA. SLC35C1 NM 001145265 Homo sapiens solute carrier family 35 (GDP-fucose 2761 transporter), member C1 (SLC35C1), transcript variant 2, mRNA. SLC35C1 NM 001145266 Homo sapiens solute carrier family 35 (GDP-fucose 2762 transporter), member C1 (SLC35C1), transcript variant 3, mRNA. SLC35C1 NM 018389 Homo sapiens solute carrier family 35 (GDP-fucose 2763 transporter), member C1 (SLC35C1), transcript variant 1, mRNA. SLC7A7 NM 001126105 Homo sapiens solute carrier family 7 (amino acid transporter 2764 light chain, y + L system), member 7 (SLC7A7), transcript variant 2, mRNA. SLC7A7 NM 001126106 Homo sapiens solute carrier family 7 (amino acid transporter 2765 light chain, y + L system), member 7 (SLC7A7), transcript variant 3, mRNA. SLC7A7 NR 040448 Homo sapiens solute carrier family 7 (amino acid transporter 2766 light chain, y + L system), member 7 (SLC7A7), transcript variant 1, non-coding RNA. SLC9A1 NM 003047 Homo sapiens solute carrier family 9, subfamily A (NHE1, 2767 cation proton antiporter 1), member 1 (SLC9A1), transcript variant 1, mRNA. SLC9A1 NR 046474 Homo sapiens solute carrier family 9, subfamily A (NHE1, 2768 cation proton antiporter 1), member 1 (SLC9A1), transcript variant 2, non-coding RNA. SMARCAL1 NM 001127207 Homo sapiens SWI/SNF related, matrix associated, actin 2769 dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1), transcript variant 2, mRNA. SMARCAL1 NM 014140 Homo sapiens SWI/SNF related, matrix associated, actin 2770 dependent regulator of chromatin, subfamily a-like 1 (SMARCAL1), transcript variant 1, mRNA. SMARCD2 NM 001098426 Homo sapiens SWI/SNF related, matrix associated, actin 2771 dependent regulator of chromatin, subfamily d, member 2 (SMARCD2), mRNA. SMC3 NM 005445 Homo sapiens structural maintenance of chromosomes 3 2772 (SMC3), mRNA. SMURF2 NM 022739 Homo sapiens SMAD specific E3 ubiquitin protein ligase 2 2773 (SMURF2), mRNA. SRP54 NM 001146282 Homo sapiens signal recognition particle 54 kDa (SRP54), 2774 transcript variant 2, mRNA. SRP54 NM 003136 Homo sapiens signal recognition particle 54 kDa (SRP54), 2775 transcript variant 1, mRNA. STN1 NM 024928.4 Homo sapiens STN1, CST complex subunit 2776 TBC1D15 NM 001146213 Homo sapiens TBC1 domain family, member 15 2777 (TBC1D15), transcript variant 3, mRNA. TBC1D15 NM 001146214 Homo sapiens TBC1 domain family, member 15 2778 (TBC1D15), transcript variant 2, mRNA. TBC1D15 NM 022771 Homo sapiens TBC1 domain family, member 15 2779 (TBC1D15), transcript variant 1, mRNA. TBC1D15 NR 027449 Homo sapiens TBC1 domain family, member 15 2780 (TBC1D15), transcript variant 4, non-coding RNA. TBC1D17 NM 001168222 Homo sapiens TBC1 domain family, member 17 2781 (TBC1D17), transcript variant 2, mRNA. TBC1D17 NM 024682 Homo sapiens TBC1 domain family, member 17 2782 (TBC1D17), transcript variant 1, mRNA. TCF3 NM 001136139 Homo sapiens transcription factor 3 (TCF3), transcript 2783 variant 2, mRNA. TCF3 NM 003200 Homo sapiens transcription factor 3 (TCF3), transcript 2784 variant 1, mRNA. TCN2 NM 000355 Homo sapiens transcobalamin II (TCN2), transcript variant 2785 1, mRNA. TCN2 NM 001184726 Homo sapiens transcobalamin II (TCN2), transcript variant 2786 2, mRNA. TEK NM 000459 Homo sapiens TEK tyrosine kinase, endothelial (TEK), 2787 mRNA. TERC NR 001566 Homo sapiens telomerase RNA component (TERC), 2788 telomerase RNA. TERT NM 001193376 Homo sapiens telomerase reverse transcriptase (TERT), 2789 transcript variant 2, mRNA. TERT NM 198253 Homo sapiens telomerase reverse transcriptase (TERT), 2790 transcript variant 1, mRNA. TFPI NM 001032281 Homo sapiens tissue factor pathway inhibitor (lipoprotein- 2791 associated coagulation inhibitor) (TFPI), transcript variant 2, mRNA. TFPI NM 006287 Homo sapiens tissue factor pathway inhibitor (lipoprotein- 2792 associated coagulation inhibitor) (TFPI), transcript variant 1, mRNA. TFRC NM 001128148 Homo sapiens transferrin receptor (p90, CD71) (TFRC), 2793 transcript variant 2, mRNA. TFRC NM 003234 Homo sapiens transferrin receptor (p90, CD71) (TFRC), 2794 transcript variant 1, mRNA. THBD NM 000361 Homo sapiens thrombomodulin (THBD), mRNA. 2795 THBS1 NM 003246 Homo sapiens thrombospondin 1 (THBS1), mRNA. 2796 TINTF2 NM 001099274 Homo sapiens TERF1 (TRF1)-interacting nuclear factor 2 2797 (TINTF2), transcript variant 1, mRNA. TINTF2 NM 012461 Homo sapiens TERF1 (TRF1)-interacting nuclear factor 2 2798 (TINTF2), transcript variant 2, mRNA. TIRAP NM 001039661 Homo sapiens toll-interleukin 1 receptor (TIR) domain 2799 containing adaptor protein (TIRAP), transcript variant 3, mRNA. TIRAP NM 148910 Homo sapiens toll-interleukin 1 receptor (TIR) domain 2800 containing adaptor protein (TIRAP), transcript variant 2, mRNA. TMC6 NM 001127198 Homo sapiens transmembrane channel-like 6 (TMC6), 2801 transcript variant 1, mRNA. TMC6 NM 007267 Homo sapiens transmembrane channel-like 6 (TMC6), 2802 transcript variant 2, mRNA. TMC8 NM 152468 Homo sapiens transmembrane channel-like 8 (TMC8), 2803 mRNA. TNFRSF17 NM 001192 Homo sapiens tumor necrosis factor receptor superfamily, 2804 member 17 (TNFRSF17), mRNA. TNFRSF1A NM 001065 Homo sapiens tumor necrosis factor receptor superfamily, 2805 member 1A (TNFRSF1A), mRNA. TNFSF10 NM 001190942 Homo sapiens tumor necrosis factor (ligand) superfamily, 2806 member 10 (TNFSF10), transcript variant 2, mRNA. TNFSF10 NM 001190943 Homo sapiens tumor necrosis factor (ligand) superfamily, 2807 member 10 (TNFSF10), transcript variant 3, mRNA. TNFSF10 NM 003810 Homo sapiens tumor necrosis factor (ligand) superfamily, 2808 member 10 (TNFSF10), transcript variant 1, mRNA. TNFSF10 NR 033994 Homo sapiens tumor necrosis factor (ligand) superfamily, 2809 member 10 (TNFSF10), transcript variant 4, non-coding RNA. TNFSF13 NM 001198622 Homo sapiens tumor necrosis factor (ligand) superfamily, 2810 member 13 (TNFSF13), transcript variant delta, mRNA. TNFSF13 NM 001198623 Homo sapiens tumor necrosis factor (ligand) superfamily, 2811 member 13 (TNFSF13), transcript variant zeta, mRNA. TNFSF13 NM 001198624 Homo sapiens tumor necrosis factor (ligand) superfamily, 2812 member 13 (TNFSF13), transcript variant eta, mRNA. TNFSF13 NM 003808 Homo sapiens tumor necrosis factor (ligand) superfamily, 2813 member 13 (TNFSF13), transcript variant alpha, mRNA. TNFSF13 NM 172087 Homo sapiens tumor necrosis factor (ligand) superfamily, 2814 member 13 (TNFSF13), transcript variant beta, mRNA. TNFSF13 NM 172088 Homo sapiens tumor necrosis factor (ligand) superfamily, 2815 member 13 (TNFSF13), transcript variant gamma, mRNA. TNFSF13 NR 073490 Homo sapiens tumor necrosis factor (ligand) superfamily, 2816 member 13 (TNFSF13), transcript variant episilon, non- coding RNA. TNFSF13B NM 001145645 Homo sapiens tumor necrosis factor (ligand) superfamily, 2817 member 13b (TNFSF13B), transcript variant 2, mRNA. TNFSF13B NM 006573 Homo sapiens tumor necrosis factor (ligand) superfamily, 2818 member 13b (TNFSF13B), transcript variant 1, mRNA. TN1P1 NM 001252385 Homo sapiens TNFAIP3 interacting protein 1 (TNIP1), 2819 transcript variant 1, mRNA. TNIP1 NM 001252386 Homo sapiens TNFAIP3 interacting protein 1 (TNIP1), 2820 transcript variant 2, mRNA. TNIP1 NM 001252390 Homo sapiens TNFAIP3 interacting protein 1 (TNIP1), 2821 transcript variant 3, mRNA. TNIP1 NM 001252391 Homo sapiens TNFAIP3 interacting protein 1 (TNIP1), 2822 transcript variant 4, mRNA. TNIP1 NM 001252392 Homo sapiens TNFAIP3 interacting protein 1 (TNIP1), 2823 transcript variant 6, mRNA. TNIP1 NM 001252393 Homo sapiens TNFAIP3 interacting protein 1 (TNIP1), 2824 transcript variant 7, mRNA. TNIP1 NM 001258454 Homo sapiens TNFAIP3 interacting protein 1 (TNIP1), 2825 transcript variant 8, mRNA. TNIP1 NM 001258455 Homo sapiens TNFAIP3 interacting protein 1 (TNIP1), 2826 transcript variant 9, mRNA. TNIP1 NM 001258456 Homo sapiens TNFAIP3 interacting protein 1 (TNIP1), 2827 transcript variant 10, mRNA. TNIP1 NM 006058 Homo sapiens TNFAIP3 interacting protein 1 (TNIP1), 2828 transcript variant 5, mRNA. TP53AIP1 NM 001195194 Homo sapiens tumor protein p53 regulated apoptosis 2829 inducing protein 1 (TP53AIP1), transcript variant 3, mRNA. TP53AIP1 NM 001195195 Homo sapiens tumor protein p53 regulated apoptosis 2830 inducing protein 1 (TP53AIP1), transcript variant 2, mRNA. TP53AIP1 NM 001251964 Homo sapiens tumor protein p53 regulated apoptosis 2831 inducing protein 1 (TP53AIP1), transcript variant 4, mRNA. TP53AIP1 NM 022112 Homo sapiens tumor protein p53 regulated apoptosis 2832 inducing protein 1 (TP53AIP1), transcript variant 1, mRNA. TPP1 NM 000391 Homo sapiens tripeptidyl peptidase I (TPP1), mRNA. 2833 TPP2 NM 003291 Homo sapiens tripeptidyl peptidase II (TPP2), mRNA. 2834 TRAF3IP2 NM 001164281 Homo sapiens TRAF3 interacting protein 2 (TRAF3IP2), 2835 transcript variant 3, mRNA. TRAF3IP2 NM 001164283 Homo sapiens TRAF3 interacting protein 2 (TRAF3IP2), 2836 transcript variant 5, mRNA. TRAF3IP2 NM 147686 Homo sapiens TRAF3 interacting protein 2 (TRAF3IP2), 2837 transcript variant 2, mRNA. TRAF3IP2 NR 028338 Homo sapiens TRAF3 interacting protein 2 (TRAF3IP2), 2838 transcript variant 1, non-coding RNA. TRIM25 NM 005082 Homo sapiens tripartite motif containing 25 (TRIM25), 2839 mRNA. TRIM37 NM 001005207 Homo sapiens tripartite motif containing 37 (TRIM37), 2840 transcript variant 2, mRNA. TRIM37 NM 015294 Homo sapiens tripartite motif containing 37 (TRIM37), 2841 transcript variant 1, mRNA. TTC37 NM 014639 Homo sapiens tetratricopeptide repeat domain 37 (TTC37), 2842 mRNA. UBD NM 006398 Homo sapiens ubiquitin D (UBD), mRNA. 2843 USB1 NM 001195302 Homo sapiens U6 snRNA biogenesis 1 (USB1), transcript 2844 variant 2, mRNA. USB1 NM 001204911 Homo sapiens U6 snRNA biogenesis 1 (USB1), transcript 2845 variant 3, mRNA. USB1 NM 024598 Homo sapiens U6 snRNA biogenesis 1 (USB1), transcript 2846 variant 1, mRNA. USP15 NM 001252078 Homo sapiens ubiquitin specific peptidase 15 (USP15), 2847 transcript variant 1, mRNA. USP15 NM 001252079 Homo sapiens ubiquitin specific peptidase 15 (USP15), 2848 transcript variant 3, mRNA. USP15 NM 006313 Homo sapiens ubiquitin specific peptidase 15 (USP15), 2849 transcript variant 2, mRNA. USP21 NM 001014443 Homo sapiens ubiquitin specific peptidase 21 (USP21), 2850 transcript variant 3, mRNA. USP21 NM 012475 Homo sapiens ubiquitin specific peptidase 21 (USP21), 2851 transcript variant 1, mRNA. USP25 NM 013396 Homo sapiens ubiquitin specific peptidase 25 (USP25), 2852 mRNA. USP3 NM 001256702 Homo sapiens ubiquitin specific peptidase 3 (USP3), 2853 transcript variant 2, mRNA. USP3 NM 006537 Homo sapiens ubiquitin specific peptidase 3 (USP3), 2854 transcript variant 1, mRNA. USP3 NR 046341 Homo sapiens ubiquitin specific peptidase 3 (USP3), 2855 transcript variant 3, non-coding RNA. USP3 NR 046342 Homo sapiens ubiquitin specific peptidase 3 (USP3), 2856 transcript variant 4, non-coding RNA. VAV1 NM 001258206 Homo sapiens vav 1 guanine nucleotide exchange factor 2857 (VAV1), transcript variant 2, mRNA. VAV1 NM 001258207 Homo sapiens vav 1 guanine nucleotide exchange factor 2858 (VAV1), transcript variant 3, mRNA. VAV1 NM 005428 Homo sapiens vav 1 guanine nucleotide exchange factor 2859 (VAV1), transcript variant 1, mRNA. VDR NM 000376 Homo sapiens vitamin D (1,25-dihydroxyvitamin D3) 2860 receptor (VDR), transcript variant 1, mRNA. VDR NM 001017535 Homo sapiens vitamin D (1,25-dihydroxyvitamin D3) 2861 receptor (VDR), transcript variant 2, mRNA. VDR NM 001017536 Homo sapiens vitamin D (1,25-dihydroxyvitamin D3) 2862 receptor (VDR), transcript variant 3, mRNA. VEGFA NM 001025366 Homo sapiens vascular endothelial growth factor A 2863 (VEGFA), transcript variant 1, mRNA. VEGFA NM 001025367 Homo sapiens vascular endothelial growth factor A 2864 (VEGFA), transcript variant 3, mRNA. VEGFA NM 001025368 Homo sapiens vascular endothelial growth factor A 2865 (VEGFA), transcript variant 4, mRNA. VEGFA NM 001025369 Homo sapiens vascular endothelial growth factor A 2866 (VEGFA), transcript variant 5, mRNA. VEGFA NM 001025370 Homo sapiens vascular endothelial growth factor A 2867 (VEGFA), transcript variant 6, mRNA. VEGFA NM 001033756 Homo sapiens vascular endothelial growth factor A 2868 (VEGFA), transcript variant 7, mRNA. VEGFA NM 001171622 Homo sapiens vascular endothelial growth factor A 2869 (VEGFA), transcript variant 8, mRNA. VEGFA NM 001171623 Homo sapiens vascular endothelial growth factor A 2870 (VEGFA), transcript variant 1, mRNA. VEGFA NM 001171624 Homo sapiens vascular endothelial growth factor A 2871 (VEGFA), transcript variant 2, mRNA. VEGFA NM 001171625 Homo sapiens vascular endothelial growth factor A 2872 (VEGFA), transcript variant 3, mRNA. VEGFA NM 001171626 Homo sapiens vascular endothelial growth factor A 2873 (VEGFA), transcript variant 4, mRNA. VEGFA NM 001171627 Homo sapiens vascular endothelial growth factor A 2874 (VEGFA), transcript variant 5, mRNA. VEGFA NM 001171628 Homo sapiens vascular endothelial growth factor A 2875 (VEGFA), transcript variant 6, mRNA. VEGFA NM 001171629 Homo sapiens vascular endothelial growth factor A 2876 (VEGFA), transcript variant 7, mRNA. VEGFA NM 001171630 Homo sapiens vascular endothelial growth factor A 2877 (VEGFA), transcript variant 8, mRNA. VEGFA NM 001204384 Homo sapiens vascular endothelial growth factor A 2878 (VEGFA), transcript variant 9, mRNA. VEGFA NM 001204385 Homo sapiens vascular endothelial growth factor A 2879 (VEGFA), transcript variant 9, mRNA. VEGFA NM 003376 Homo sapiens vascular endothelial growth factor A 2880 (VEGFA), transcript variant 2, mRNA. WASHC5 NM 001330609.1 Homo sapiens WASH complex subunit 5, transcript variant 2881 2 WASHC5 NM 014846.3 Homo sapiens WASH complex subunit 5, transcript variant 2882 1 WDR1 NM 005112 Homo sapiens WD repeat domain 1 (WDR1), transcript 2883 variant 2, mRNA. WDR1 NM 017491 Homo sapiens WD repeat domain 1 (WDR1), transcript 2884 variant 1, mRNA. WRAP53 NM 001143990 Homo sapiens WD repeat containing, antisense to TP53 2885 (WRAP53), transcript variant 2, mRNA. WRAP53 NM 001143991 Homo sapiens WD repeat containing, antisense to TP53 2886 (WRAP53), transcript variant 3, mRNA. WRAP53 NM 001143992 Homo sapiens WD repeat containing, antisense to TP53 2887 (WRAP53), transcript variant 4, mRNA. WRAP53 NM 018081 Homo sapiens WD repeat containing, antisense to TP53 2888 (WRAP53), transcript variant 1, mRNA. XAF1 NM 017523 Homo sapiens XIAP associated factor 1 (XAF1), transcript 2889 variant 1, mRNA. XAF1 NM 199139 Homo sapiens XIAP associated factor 1 (XAF1), transcript 2890 variant 2, mRNA. XAF1 NR 046396 Homo sapiens XIAP associated factor 1 (XAF1), transcript 2891 variant 3, non-coding RNA. XAF1 NR 046397 Homo sapiens XIAP associated factor 1 (XAF1), transcript 2892 variant 4, non-coding RNA. XAF1 NR 046398 Homo sapiens XIAP associated factor 1 (XAF1), transcript 2893 variant 5, non-coding RNA. Table 32 represents a non-redundant list of transcript variants that correspond to the Table 31 genes.

TABLE 33 SEQ ID 3000-3274, SNV list (Tables 34-36, 38, 39) with SEQ ID numbers (similar to Table 5) Chromosome Position (hg19) Ref Allele Alt Allele SEQ ID 1 11087369 T C 3000 1 11090287 C T 3001 1 11090916 C A 3002 1 11094908 T A 3003 1 11106648 G A 3004 1 11106666 T C 3005 1 11106673 G A 3006 1 12049283 C T 3007 1 12064892 G A 3008 1 12064931 G A 3009 1 57333311 C A 3010 1 57372463 C T 3011 1 57373778 G A 3012 1 57378149 G T 3013 1 57383295 G A 3014 1 57409459 C A 3015 1 57422511 C T 3016 1 59131311 G T 3017 1 82409337 A G 3018 1 82416040 C T 3019 1 82450271 G A 3020 1 82456165 G T 3021 1 160281740 T C 3022 1 183532364 T A 3023 1 196709774 G T 3024 1 196759282 C T 3025 1 196794681 G T 3026 1 196799813 G A 3027 1 196871610 A T 3028 1 196918732 G T 3029 1 196920123 G A 3030 1 196973890 G A 3031 2 7027110 G T 3032 2 15432775 C T 3033 2 15519924 C T 3034 2 15542352 C T 3035 2 15607842 T C 3036 2 15674686 T C 3037 2 47637246 A G 3038 2 47702191 A G 3039 2 74688563 C T 3040 2 74688884 G A 3041 2 74689335 G T 3042 2 74690039 G A 3043 2 74690371 C T 3044 2 74690378 C T 3045 2 109381493 G C 3046 2 109382448 C T 3047 2 109384800 C T 3048 2 188349523 A G 3049 2 217285060 C G 3050 2 217285104 C G 3051 2 217288388 G C 3052 3 11382205 A C 3053 3 11399970 C T 3054 3 11402163 G A 3055 3 11468330 A G 3056 3 20017123 A C 3057 3 37061893 T C 3058 3 37061929 A G 3059 3 37092025 C T 3060 3 39452455 C T 3061 3 48457498 G C 3062 3 48461135 C T 3063 3 48463544 G A 3064 3 49949430 C T 3065 3 171321023 C T 3066 3 171379953 C T 3067 3 171431726 C G 3068 3 171455697 G C 3069 3 171455739 A G 3070 4 89352440 A C 3071 4 89414196 G A 3072 4 110864533 C T 3073 4 110865044 G C 3074 4 110866260 G C 3075 4 110897252 C G 3076 4 110929301 T C 3077 4 110932508 C A 3078 4 126237697 A C 3079 4 126238090 G T 3080 4 126238305 C A 3081 4 126239241 G A 3082 4 126239253 G C 3083 4 126239421 C T 3084 4 126239623 G A 3085 4 126239986 C T 3086 4 126240255 A G 3087 4 126240377 G T 3088 4 126240390 A G 3089 4 126240968 A T 3090 4 126241248 C G 3091 4 126241720 T C 3092 4 126241785 G A 3093 4 126328170 C T 3094 4 126336758 G A 3095 4 126336851 G A 3096 4 126372003 A G 3097 4 126372975 A C 3098 4 126373570 C T 3099 4 126389832 G A 3100 4 126408663 A G 3101 4 126411179 C T 3102 4 126411493 C T 3103 4 126412106 C G 3104 4 126412154 G A 3105 4 126412226 G A 3106 4 126412634 C G 3107 5 34929974 A T 3108 5 34937524 C T 3109 5 39311336 A T 3110 5 40955561 G C 3111 5 40959622 C T 3112 5 40964852 A C 3113 5 131925413 A G 3114 5 132015535 C T 3115 5 134076987 G C 3116 6 30673403 A G 3117 6 30675830 T A 3118 6 30680721 G A 3119 6 31593603 A G 3120 6 31595795 C T 3121 6 31595926 C T 3122 6 31597451 G A 3123 6 31597469 A C 3124 6 31598524 G A 3125 6 31599370 G C 3126 6 31600118 G A 3127 6 31600558 C T 3128 6 31600696 G A 3129 6 31600708 G A 3130 6 31601735 G A 3131 6 31602967 G A 3132 6 31603045 A G 3133 6 31604591 C T 3134 6 31604610 T C 3135 6 31604894 C T 3136 6 31605016 T C 3137 6 31605278 C T 3138 6 31709045 C T 3139 6 31725978 C G 3140 6 31729925 C T 3141 6 43748510 G A 3142 6 106740989 T C 3143 6 111913058 G A 3144 6 111913262 C T 3145 7 5959528 T C 3146 7 30491421 G T 3147 7 30491693 C T 3148 7 74193620 G A 3149 7 80300449 T G 3150 7 92732769 T C 3151 7 92733766 C A 3152 7 92761257 A T 3153 7 92763720 G A 3154 7 117230454 G C 3155 7 117232086 G A 3156 7 117232223 C T 3157 7 117246776 T C 3158 8 11400805 C A 3159 8 11400849 C T 3160 8 11407690 C T 3161 8 11412934 G A 3162 8 11415492 A C 3163 8 11418856 C T 3164 8 126071726 G A 3165 8 126095371 T C 3166 9 27109600 A C 3167 9 27158131 C T 3168 9 27183598 C T 3169 9 27197588 C T 3170 9 35612978 G A 3171 9 98678698 G C 3172 9 98691137 T C 3173 10 54531226 C T 3174 10 54531235 C T 3175 10 54531242 G A 3176 10 75672059 G A 3177 10 75673748 A C 3178 10 75675086 T C 3179 10 91098614 G A 3180 10 91162073 T C 3181 11 60891358 C T 3182 11 60893235 C T 3183 11 65423327 G A 3184 11 72145307 C G 3185 11 119045378 C T 3186 11 119045951 C T 3187 11 119052975 G T 3188 11 128807550 C G 3189 12 25362788 T A 3190 12 25368449 A T 3191 12 40657700 C G 3192 12 40671773 A G 3193 12 40677813 G T 3194 12 40702420 A G 3195 12 40702910 C T 3196 12 40702911 G A 3197 12 40740686 A G 3198 12 49421042 C T 3199 12 49421811 C A 3200 12 49428694 T C 3201 12 49433083 G A 3202 12 49433533 G C 3203 12 49440564 C T 3204 12 56383856 A G 3205 12 56385915 GGGA G 3206 12 113357209 G A 3207 12 113357237 G C 3208 12 113357442 G A 3209 12 113403675 C T 3210 12 113405825 G A 3211 12 113448288 A G 3212 14 35497285 T C 3213 14 94847262 T A 3214 15 63866584 C A 3215 15 93545488 T A 3216 16 11145457 G A 3217 16 11272435 G A 3218 16 14704607 G A 3219 16 23693443 C T 3220 16 23700676 T A 3221 16 58054099 C G 3222 16 67680806 G A 3223 16 67685730 A T 3224 16 67694044 C T 3225 16 67694078 G T 3226 16 69725697 T G 3227 16 77225440 G T 3228 17 6659427 C A 3229 17 7592168 C G 3230 17 8138569 C G 3231 17 41165632 G A 3232 17 43555253 A G 3233 17 62582265 T C 3234 17 76129619 C T 3235 17 76130947 G T 3236 18 29645930 A T 3237 18 57103126 G A 3238 18 61570402 G A 3239 19 6707129 G A 3240 19 7754222 G A 3241 19 10394724 C T 3242 19 10395141 G A 3243 19 15383894 C G 3244 19 33892731 A G 3245 19 33968991 T A 3246 19 33980963 G A 3247 19 35823528 C T 3248 19 44153248 T C 3249 19 49843566 G A 3250 19 50385633 G C 3251 19 55494157 G A 3252 20 39794388 T C 3253 20 44640275 G A 3254 20 44640959 G A 3255 21 35122475 C T 3256 21 35239562 A G 3257 21 42752030 G A 3258 21 42807815 A G 3259 21 42807881 G A 3260 21 42812952 G A 3261 21 42813652 C A 3262 21 42815731 G A 3263 21 42817460 C T 3264 21 42830468 G A 3265 21 42830657 G A 3266 21 45708270 T C 3267 21 45708278 G A 3268 21 45713696 G A 3269 22 31006882 T G 3270 22 31008867 T C 3271 22 31018975 T C 3272 22 35806756 G A 3273 22 37271882 T C 3274 Table 33 lists a set of SNVs reported in Tables 34-36, 38, or 39 that were found in the 70 PML cases for the genes listed in Table 31.

TABLE 34 Case-solving Tier 1 SNVs (het, hom, or phased comp het) with frequency <=1/1,000 or novel Compound Variant Variant Compound Frequency Frequency Frequency Frequency RefSeq Chro- Amino Details (Reciprocal, Details (Reciprocal, Gene Variant mo- Position Ref Alt Acid (Ethnic Ethnic (Ethnic Ethnic SEQ Sample ID Symbol Type some (hg19) Allele Allele Change specific) specific) specific) specific) ID MVGS1116-8a PRRCA SNV het 6 31601735 G A R1563Q 0.087118 1 in 11 7.40E−04 1 in 1,350 3131 MVGS1116-8a PRRCA SNV het 6 31604894 C T R2075W 0.034000 1 in 29 7.40E−04 1 in 1,350 3136 MVGS1368 KMT2D SNV het 12 49421811 C A K4832N 0.000240 1 in 4,167 n/a n/a 3200 MVGS540-374b ATG7 SNV het 3 11382205 A C K287Q 6.14E−05 1 in 16,292 n/a n/a 3053 MVGS540-374b KMT2D SNV het 12 49433533 G C Q2674E 0 infinite n/a n/a 3203 MVGS694-6a AIRE SNV het 21 45708270 T C M194T 0 infinite n/a n/a 3267 MVGS811-13a LRRK2 SNV het 12 40702910 C T R1398C 6.01E−05 1 in 16,646 2.09E−06 1 in 477,620 3196 MVGS811-13a LRRK2 SNV het 12 40702911 G A R1398H 0.139408 1 in 7 2.09E−06 1 in 477,620 3197 MVGS811-13a USP3 SNV het 15 63866584 C A P111T 0.000513 1 in 1,950 n/a n/a 3215 MVGS995-4a VEGFA SNV het 6 43748510 G A R155H 3.00E−05 1 in 33,364 n/a n/a 3142 PML04 RSAD2 SNV het 2 7027110 G T E117* 0 infinite n/a n/a 3032 PML04 IFIT1 SNV het 10 91162073 T C L14P 0 infinite n/a n/a 3181 PML04 CLEC16A SNV het 16 11145457 G A V634M 0.000120 1 in 8,339 n/a n/a 3217 PML06 LRRK2 SNV hom 12 40657700 C G N299K 0.018554 1 in 54 1.19E−05 1 in 84,337 3192 PML06 LRRK2 SNV hom 12 40671773 A G I423M 0.000194 1 in 5,159 see het SNVs see het SNVs 3193 PML06 LRRK2 SNV hom 12 40702911 G A R1398H 0.019646 1 in 51 1.17E−05 1 in 85,236 3197 PML06 CD37 SNV hom 19 49843566 G A R208Q 0.000194 1 in 5,165 n/a n/a 3250 PML09 FAT4 SNV hom 4 126239986 C T A807V 0.196043 1 in 5 0.000273 1 in 3,665 3086 PML09 FAT4 SNV het 4 126241248 C G Q1228E 0.002227 1 in 449 0.000273 1 in 3,665 3091 PML09 PRRC2A SNV het 6 31600118 G A R1223H 0 infinite n/a n/a 3127 PML10 ATG7 SNV het 3 11468330 A G N643S 0 infinite n/a n/a 3056 PML10 PRRC2A SNV het 6 31597469 A C K701Q 0.000186 1 in 5,385 n/a n/a 3124 PML14 KRAS SNV het 12 25362788 T A M170L 3.03E−05 1 in 33,044 n/a n/a 3190 PML15 CFHR1 SNV hom 1 196794681 G T V45F 0.000182 1 in 5,509 n/a n/a 3026 PML15 CFHR1 SNV hom 1 196799813 G A n/a 0.000175 1 in 5,711 n/a n/a 3027 PML15 PRRC2A SNV het 6 31598524 G A R804H 0 infinite n/a n/a 3125 PML15 MBL2 SNV hom 10 54531226 C T G57E 0.000518 1 in 9,929 n/a n/a 3174 PML16 IFIT3 SNV het 10 91098614 G A E68K 0 infinite n/a n/a 3180 PML17 TEK SNV het 9 27109600 A C L4F 8.99E−05 1 in 11,123 n/a n/a 3167 PML17 TEK SNV het 9 27158131 C T R119C 0 infinite n/a n/a 3168 PML18 OAS3 SNV hom 12 113403675 C T R844* 0.000277 1 in 3,611 n/a n/a 3210 PML19 MASP2 SNV het 1 11087369 T C N545S 0 infinite 0 infinite 3000 PML19 MASP2 SNV hom 1 11090916 C A D371Y 0.070713 1 in 14 see het SNV see het SNV 3002 PML19 ADGRL2 SNV het 1 82450271 G A R1017Q 0 infinite n/a n/a 3020 PML23 RANB2 SNV het 2 109352448 C T P1818L 3.00E−05 1 in 33,362 n/a n/a 3047 PML25 ATG7 SNV het 3 11399970 C T R416C 6.00E−05 1 in 16,676 n/a n/a 3054 PML25 IL4 SNV het 5 132015535 C T R105* 0 infinite n/a n/a 3115 PML27 MLH1 SNV het 3 37061929 A G N240S 0.000180 1 in 5,543 n/a n/a 3059 PML28 MSH2 SNV het 2 47702191 A G N530S 0.000631 1 in 1,586 n/a n/a 3039 PML28 FAT4 SNV het 4 126239623 G A S686N 5.99E−05 1 in 16,684 7.35E−06 1 in 136,129 3085 PML28 FAT4 SNV het 4 126239986 C T A807V 0.490241 1 in 2 7.35E−06 1 in 136,129 3086 PML30 MON1A SNV het 3 49949430 C T G145S 0.000720 1 in 1,388 n/a n/a 3065 PML31 CFHR5 SNV het 1 196973890 G A R477H 0.000577 1 in 1,734 n/a n/a 3031 PML31 FAT4 SNV het 4 126239253 G C V563L 0 infinite 0 infinite 3083 PML31 FAT4 SNV hom 4 126239986 C T A807V 0.325510 1 in 3 see het SNVs see het SNVs 3086 PML31 FAT4 SNV het 4 126328170 C T R113C 0 infinite 0 infinite 3094 PML31 FAT4 SNV het 4 126372003 A G R1576G 0 infinite 0 infinite 3097 PML31 PRRC2A SNV het 6 31593603 A G Y265C 0 infinite n/a n/a 3120 PML31 PRRC2A SNV hom 6 31602967 G A R1740H 0 1 in 4 see het SNV see het SNV 3132 PML31 RNF125 SNV hom 18 29645930 A T R190S 0.258362 1 in 5,203 n/a n/a 3237 PML31 PLCG1 SNV het 20 39794388 T C I574T 0 infinite n/a n/a 3253 PML32 FAT4 SNV hom 4 126239986 C T A807V 0.196043 1 in 5 see het SNV see het SNV 3086 PML32 FAT4 SNV het 4 126412226 G A G2991E 0 infinite 0 infinite 3106 PML33 PRRC2A SNV het 6 31600558 C T R1370C 3.16E−05 1 in 31,613 n/a n/a 3128 PML33 KMT2D SNV het 12 49440564 C T V1416M 0 infinite n/a n/a 3204 PML35 TP53AIP1 SNV het 11 128807550 C G R55P 0.000210 1 in 4,763 n/a n/a 3189 PML35 MX1 SNV het 21 42813652 C A T224K 0 infinite n/a n/a 3262 PML37 FAT4 SNV het 4 126239986 C T A807V 0.325510 1 in 3 2.36E−05 1 in 42,385 3086 PML37 FAT4 SNV het 4 126336758 G A A2214T 0.000192 1 in 5,203 2.36E−05 1 in 42,385 3095 PML38 PRRC2A SNV het 6 31597451 G A A695T 0 infinite n/a n/a 3123 PML38 MX1 SNV het 21 42830657 G A R631Q 3.07E−05 1 in 32,566 n/a n/a 3266 PML39 PRRC2A SNV het 6 31600708 G A G1420R 0 infinite n/a n/a 3130 PML40 COPA SNV het 1 160281740 T C M332V 0.000692 1 in 1,444 n/a n/a 3200 PML40 MSH2 SNV hom 2 47637246 A G N127S 0 infinite n/a n/a 3038 PML40 TBC1D17 SNV het 19 50385633 G C E225D 0 infinite n/a n/a 3251 PML41 MLH1 SNV het 3 37061893 T C V228A 0.000577 1 in 1,734 n/a n/a 3058 PML41 SAMD9L SNV het 7 92761257 A T L134H 0 infinite n/a n/a 3153 PML41 SMURF2 SNV het 17 62582265 T C I129V 0 infinite n/a n/a 3234 PML43 KRAS SNV het 12 25368449 A T Y166N 0.000300 1 in 3,335 n/a n/a 3191 PML44 RAB5A SNV het 3 20017123 A C D65N 3.01E−05 1 in 33,252 n/a n/a 3057 PML44 PLXNB1 SNV het 3 48461135 C T E854K 0.000705 1 in 1,419 n/a n/a 3063 PML44 NLRX1 SNV het 11 119045378 C T R356W 0.000992 1 in 1,008 n/a n/a 3186 PML45 C7 SNV het 5 40955561 G C S389T 0.472838 1 in 2 3.97E−06 1 in 251,629 3111 PML45 C7 SNV het 5 40959622 C T R521C 3.36E−05 1 in 29,745 3.97E−06 1 in 251,629 3112 PML45 WASHC5 SNV het 9 126071726 G A T379I 3.03E−05 1 in 32,985 n/a n/a 3165 PML45 BRD4 SNV het 19 15383894 C G G6A 9.24E−05 1 in 10,823 n/a n/a 3244 PML48 NCF1 SNV hom 7 74193620 G A G83R 6.32E−05 1 in 15,829 n/a n/a 3149 PML48 MX1 SNV het 21 42807815 A G I53V 0.000120 1 in 8,339 n/a n/a 3259 PML49 RPSA SNV het 3 39452455 C T R155V 0 infinite n/a n/a 3061 PML49 BLK SNV het 8 11400805 C A S24R 3.02E−05 1 in 33,067 n/a n/a 3159 PML51 NBAS SNV hom 2 15519924 C T R1011H 0.000839 1 in 1,191 n/a n/a 3034 PML52 KMT2D SNV het 12 49433083 G A P2763L 0 infinite n/a n/a 3202 PML52 MX1 SNV het 21 42830468 G A R568H 0.000391 1 in 2,559 n/a n/a 3265 PML54 PARN SNV het 16 14704607 G A R104C 0.000120 1 in 8,342 n/a n/a 3219 PML55 PLXNB1 SNV het 3 48457498 G C L1004V 0 infinite n/a n/a 3062 PML55 FAT4 SNV het 4 126412106 C G S2951C 0.037914 1 in 26 0.000400 1 in 2,501 3104 PML55 FAT4 SNV het 4 126412154 G A R2967K 0.042189 1 in 24 0.000400 1 in 2,501 3105 PML56 PRRC2A SNV hom 6 31603045 A G D1766G 0.001000 1 in 1,000 n/a n/a 3133 PML56 OAS3 SNV het 12 113405825 G A G155R 6.00E−05 1 in 16,672 n/a n/a 3211 PML57 CD5 SNV het 11 60891358 C T R410C 0.000183 1 in 5,475 n/a n/a 3182 PML57 ITSN1 SNV het 21 35122475 C T P125L 3.04E−05 1 in 32,871 n/a n/a 3256 PML58 MASP2 SNV het 1 11106648 G A P126L 0.216611 1 in 5 see het SNV see het SNV 3004 PML58 MASP2 SNV het 1 11106673 G A R11C 0 infinite 0 infinite 3006 PML59 CAMLG SNV het 5 134076987 G C R136T 0 infinite n/a n/a 3116 PML60 RELA SNV het 11 65423327 G A n/a 0.000300 1 in 3,337 n/a n/a 3184 PML62 KMT2D SNV het 12 49421042 C T V4903M 0 infinite n/a n/a 3199 PML63 PLD1 SNV het 3 171455697 G C P49A 0.033699 1 in 30 3.05E−04 1 in 3,276 3069 PML63 PLD1 SNV het 3 171455739 A G F35L 0.011729 1 in 85 3.05E−04 1 in 3,276 3070 PML64 MFN2 SNV het 1 12049283 C T H20Y 0 infinite n/a n/a 3007 PML65 FAT4 SNV het 4 126239421 C T R619C 0.006117 1 in 163 0.000751 1 in 1,332 3084 PML65 FAT4 SNV hom 4 126239986 C T A807V 0.325510 1 in 3 0.000751 1 in 1,332 3086 PML65 XAF1 SNV het 17 6659427 C A N10K 0 infinite n/a n/a 3229 PML66 MFN2 SNV het 1 12064931 G A R481H 0 infinite n/a n/a 3009 PML66 ADGRL2 SNV het 1 72409337 A G Q228R 0.000192 1 in 5,201 n/a n/a 3018 PML66 PLXNB1 SNV het 3 48463544 G A P497L 0 infinite n/a n/a 3064 PML66 MX1 SNV het 21 42817460 C T P342L 0 infinite n/a n/a 3264 PML72 MX1 SNV het 21 42812952 G A G221R 0 infinite n/a n/a 3261 Table 34 lists potential cause(s) of PML in the study, SNVs (het, horn, or phased comp het) for genes in Table 31 with frequency <=1/1,000 or novel.

TABLE 35 Case-solving Tier 2 SNVs (het, hom, or phased comp het) with frequency <=1/1,00 but >1/1,000 Fre- Compound Variant quency Variant Compound Frequency (Recip- Frequency Frequency RefSeq Chro- Amino Details rocal, Details (Reciprocal, Sample Gene Variant mo- Position Ref Alt Acid (Ethnic Ethnic (Ethnic Ethnic SEQ ID Symbol Type some (hg19) Allele Allele Change specific) specific) specific) specific) ID MVG RNF125 SNV 18 29645930 A T R190S 0.004555 1 in 220 n/a n/a 3237 S1116- het 8a MVG BLK SNV 8 11415492 A C K254T 0.004497 1 in 222 n/a n/a 3163 S540- het 374b MVG PRRC2A SNV 6 31604591 C T P2006S 0.282199 1 in 4 0.002399 1 in 417 3134 S540- het 393b MVG PRRC2A SNV 6 31604894 C T R2075W 0.034000 1 in 29 0.002399 1 in 417 3136 S540- het 393b MVG PRRC2A SNV 6 31602967 G A R1740H 0.115236 1 in 9 see het see het 3132 S811- hom SNV SNV 13a MVG PRRC2A SNV 6 31605278 C T P2130L 0.045577 1 in 22 0.005004 1 in 200 3138 S811- het 13a PML PLK1 SNV 16 23693443 C T L21F 0.006119 1 in 163 n/a n/a 3220 01 het PML PRRC2A SNV 6 31595926 C T P559S 0.007481 1 in 134 n/a n/a 3122 02 het PML ADGRL2 SNV 1 82456165 G T G1130V 0.002578 1 in 388 n/a n/a 3021 04 het PML PRRC2A SNV 6 31595795 C T P515L 0.009777 1 in 102 0.001131 1 in 884 3121 05 het PML PRRC2A SNV 6 31602967 G A R1740H 0.149550 1 in 7 see het see het 3132 05 hom SNV SNV PML NOD1 SNV 7 30491693 C T R447H 0.006746 1 in 148 n/a n/a 3148 05 het PML CD72 SNV 9 35612978 G A P234L 0.001558 1 in 642 n/a n/a 3171 05 hom PML MON1B SNV 16 77225440 G T D20Y 0.009826 1 in 102 n/a n/a 3228 05 het PML MX2 SNV 21 42752030 G A E177K 0.002074 1 in 482 n/a n/a 3258 05 het PML MASP2 SNV 1 11090916 C A D371Y 0.655818 1 in 2 see het see het 3002 09 hom SNV SNV PML MASP2 SNV 1 11106666 T C D120G 0.062380 1 in 16 0.004783 1 in 209 3005 09 het PML MASP2 SNV 1 11090916 C A D371Y 0.655818 1 in 2 see het see het 3002 10 hom SNV SNV PML MASP2 SNV 1 11106666 T C D120G 0.062380 1 in 16 0.004783 1 in 209 3005 10 het PML MFN2 SNV 1 12064892 G A R468H 0.006444 1 in 155 n/a n/a 3008 10 het PML BLK SNV 8 11400849 C T P39L 0.006656 1 in 150 n/a n/a 3160 10 het PML RNF125 SNV 18 29645930 A T R190S 0.004555 1 in 220 n/a n/a 3237 10 het PML ADGRL2 SNV 1 82416040 C T P323S 0.005425 1 in 184 n/a n/a 3019 13 het PML LRRK2 SNV 12 40740686 A G N2081D 0.005082 1 in 197 n/a n/a 3198 13 het PML MMP9 SNV 20 44640275 G A G296S 0.001154 1 in 867 n/a n/a 3254 13 het PML MBL2 SNV 10 54531235 C T G54D 0.248456 1 in 4 0.008625 1 in 116 3175 14 het PML MBL2 SNV 10 54531242 G A R52C 0.138866 1 in 7 0.008625 1 in 116 3176 14 het PML CFHR2 SNV 1 196920123 G A R116Q 0.001567 1 in 638 n/a n/a 3030 15 het PML RANBP2 SNV 2 109381493 G C A1500P 0.008681 1 in 115 n/a n/a 3046 16 het PML PRRC2A SNV 6 31604610 T C V2012A 0.001126 1 in 888 n/a n/a 3135 16 het PML AIRE SNV 21 45708278 G A G197R 0.002143 1 in 467 n/a n/a 3268 16 het PML WASHC5 SNV 8 126095371 T C I106V 0.001990 1 in 502 n/a n/a 3166 18 het PML SAMD9L SNV 7 92763720 G A A522V 0.006869 1 in 146 n/a n/a 3154 19 het PML C8B SNV 1 57422511 C T E108K 0.002691 1 in 372 n/a n/a 3016 20 hom PML HERC5 SNV 4 89414196 G A G361R 0.003652 1 in 274 n/a n/a 3072 20 het PML FAT4 SNV 4 126239986 C T A807V 0.491020 1 in 2 0.004487 1 in 223 3086 20 het PML FAT4 SNV 4 126241785 G A V1407I 0.036553 1 in 27 0.004487 1 in 223 3093 20 het PML PRRC2A SNV 6 31595795 C T P515L 0.022579 1 in 44 0.002872 1 in 348 3121 20 het PML PRRC2A SNV 6 31602967 G A R1740H 0.258362 1 in 4 see het see het 3132 20 hom SNVs SNVs PML CCZ1 SNV 7 5959528 T C V203A 0.007045 1 in 142 n/a n/a 3146 20 het PML C8A SNV 1 57378149 G T R485L 0.001712 1 in 584 n/a n/a 3013 22 hom PML LRRK2 SNV 12 40657700 C G N299K 0.006768 1 in 148 n/a n/a 3192 23 hom PML LRRK2 SNV 12 40702911 G A R1398H 0.006697 1 in 149 n/a n/a 3197 23 hom PML FAT4 SNV 4 126239986 C T A807V 0.196043 1 in 5 see het see het 3086 26 hom SNV SNV PML FAT4 SNV 4 126373570 C T S2098F 0.088450 1 in 11 0.010840 1 in 92 3099 26 het PML FAT4 SNV 4 126239986 C T A807V 0.325510 1 in 3 see het see het 3086 31 hom SNV SNV PML FAT4 SNV 4 126389832 G A R2285Q 0.056972 1 in 18 0.006994 1 in 143 3100 31 het PML RAB5B SNV 12 56383856 A G I97V 0.003416 1 in 293 n/a n/a 3205 31 het PML FCER2 SNV 19 7754222 G A R274C 0.004261 1 in 235 n/a n/a 3241 31 het PML C3 SNV 19 6707129 G A R735W 0.006398 1 in 156 n/a n/a 3240 32 het PML BLK SNV 8 11412934 G A R167Q 0.008846 1 in 113 n/a n/a 3162 33 het PML CHD2 SNV 15 93545488 T A S1407T 0.004813 1 in 208 n/a n/a 3216 36 het PML PLK1 SNV 16 23700676 T A L463H 0.004422 1 in 226 n/a n/a 3221 36 het PML MASP2 SNV 1 11090287 C T D415N 0.036717 1 in 27 0.003304 1 in 303 3001 37 het PML MASP2 SNV 1 11090916 C A D371Y 0.359923 1 in 3 0.003304 1 in 303 3002 37 het PML MOGS SNV 2 74688884 G A R572W 0.008575 1 in 117 n/a n/a 3041 37 hom PML FAT4 SNV 4 126239986 C T A807V 0.325510 1 in 3 see het see het 3086 37 hom SNVs SNVs PML FAT4 SNV 4 126240377 G T K937N 0.021429 1 in 47 0.002630 1 in 380 3088 37 het PML FAT4 SNV 4 126408663 A G D2568G 0.031611 1 in 32 0.003880 1 in 258 3101 37 het PML LRRK2 SNV 12 40702420 A G I1371V 0.001055 1 in 948 n/a n/a 3195 38 het PML MMP9 SNV 20 44640275 G A G296S 0.005222 1 in 191 n/a n/a 3254 38 het PML CFHR4 SNV 1 196871610 A T R40* 0.005310 1 in 188 n/a n/a 3028 39 het PML CD36 SNV 7 80300449 T G Y249* 0.009686 1 in 103 n/a n/a 3150 39 hom PML NLRX1 SNV 11 119052975 G T A843S 0.001182 1 in 846 n/a n/a 3188 39 hom PML ICAM1 SNV 19 10394724 C T P218L 0.003194 1 in 313 n/a n/a 3242 39 het PML MLH1 SNV 3 37092025 C T H477Y 0.003985 1 in 251 n/a n/a 3060 40 het PML NOD1 SNV 7 30491693 C T R447H 0.006746 1 in 148 n/a n/a 3148 40 het PML TEK SNV 9 27183598 C T T201I 0.002950 1 in 339 n/a n/a 3169 40 het PML NLRX1 SNV 11 119052975 G T A843S 0.001734 1 in 577 n/a n/a 3188 40 het PML MX1 SNV 21 42815731 G A G293R 0.002418 1 in 414 n/a n/a 3263 40 het PML PLAU SNV 10 75675086 T C Y314H 0.001730 1 in 578 n/a n/a 3179 41 het PML IFI35 SNV 17 41165632 G A R172Q 0.002886 1 in 347 n/a n/a 3232 41 het PML SERPINB2 SNV 18 61570402 G A A371T 0.002162 1 in 463 n/a n/a 3239 43 het PML RAD50 SNV 5 131925413 A G K307E 0.001430 1 in 700 n/a n/a 3114 45 het PML MX1 SNV 21 42807881 G A V75I 0.001409 1 in 710 n/a n/a 3260 45 het PML NLRX1 SNV 11 119045951 C T R547W 0.001904 1 in 525 n/a n/a 3187 46 het PML NFAT5 SNV 16 69725697 T G S563A 0.005437 1 in 184 n/a n/a 3227 48 het PML LRRK2 SNV 12 40677813 G T R793M 0.001409 1 in 710 n/a n/a 3194 49 het PML TEK SNV 9 27197588 C T L444F 0.002243 1 in 446 n/a n/a 3170 51 het PML USB1 SNV 16 58054099 C G Q199E 0.007344 1 in 136 n/a n/a 3222 52 hom PML PRRC2A SNV 6 31599370 G C E974Q 0.002791 1 in 358 n/a n/a 3126 53 het PML RANBP2 SNV 2 109384800 C T T2602M 0.003726 1 in 268 n/a n/a 3048 54 het PML FAT4 SNV 4 126239986 C T A807V 0.196043 1 in 5 see het see het 3086 54 hom SNVs SNVs PML FAT4 SNV 4 126372975 A C I1900L 0.022291 1 in 45 0.002732 1 in 366 3098 54 het PML FAT4 SNV 4 126373570 C T S2098F 0.088450 1 in 11 0.010840 1 in 92 3099 54 het PML BLK SNV 8 11418856 C T R288C 0.002025 1 in 494 n/a n/a 3164 56 het PML MSH5 SNV 6 31709045 C T L85F 0.001200 1 in 833 n/a n/a 3139 56 hom PML MSH5 SNV 6 31729925 C T P108S 0.001409 1 in 710 n/a n/a 3141 56 hom PML KMT2D SNV 12 49428694 T C D3419G 0.004830 1 in 207 n/a n/a 3201 56 het PML CD22 SNV 19 35823528 C T A36V 0.002712 1 in 369 n/a n/a 3248 61 het PML CFH SNV 1 196709774 G T E936D 0.004036 1 in 248 n/a n/a 3024 62 hom PML FAT4 SNV 4 126239986 C T A807V 0.325510 1 in 3 see het see het 3086 63 hom SNV SNV PML FAT4 SNV 4 126389832 G A R2285Q 0.056972 1 in 18 0.006994 1 in 143 3100 63 het PML ACD SNV 16 67694078 G T L102M 0.002049 1 in 488 n/a n/a 3226 63 het PML AIRE SNV 21 45713696 G A G228R 0.001432 1 in 698 n/a n/a 3269 63 het PML PLAU SNV 10 75672059 G A G41R 0.001953 1 in 512 n/a n/a 3177 64 het PML HERC6 SNV 4 89352440 A C M709L 0.002213 1 in 452 n/a n/a 3071 66 het PML RANBP2 SNV 2 109384800 C T T2602M 0.003726 1 in 268 n/a n/a 3048 68 het PML BLK SNV 8 11407690 C T R131W 0.001589 1 in 629 n/a n/a 3161 68 het PML CFHR2 SNV 1 196918732 G T R69L 0.007311 1 in 137 n/a n/a 3029 72 het PML CLEC16A SNV 16 11272435 G A S1017N 0.008537 1 in 117 n/a n/a 3218 72 het Table 35 lists potential cause(s) of PML in the study, SNVs (het, horn, or phased comp het) for genes in Table 31 with frequency <=1/1,00 but >1/1,000.

TABLE 36 Case-solving un-phased potential comp het SNVs with comp het frequency <=1/1,00 Predicted Com- Fre- pound Predicted Variant quency Variant Compound Frequency (Recip- Frequency Frequency RefSeq Chro- Amino Details rocal, Details (Reciprocal, Sample Gene Variant mo- Position Ref Alt Acid (Ethnic Ethnic (Ethnic Ethnic SEQ ID Symbol Type some (hg19) Allele Allele Change specific) specific) specific) specific) ID MVG DNAJC21 SNV 5 34929974 A T E17V 0 infinite 0 infinite 3108 S1359 het MVG DNAJC21 SNV 5 34937524 C T R178C 0 infinite 0 infinite 3109 S1359 het MVG PRRC2A SNV 6 31602967 G A R1740H 0.439204 1 in 2 0.005004 1 in 200 3132 S1368 het MVG PRRC2A SNV 6 31605278 C T P2130L 0.045577 1 in 22 0.005004 1 in 200 3138 S1368 het MVG PRRC2A SNV 6 31602967 G A R1740H 0.439204 1 in 2 0.003733 1 in 268 3132 S540- het 393b MVG PRRC2A SNV 6 31604894 C T R2075W 0.034000 1 in 29 0.003733 1 in 268 3136 S540- het 393b MVG CFTR SNV 7 117230454 G C G515A 0.015182 1 in 66 6.99E−05 1 in 14,314 3155 S540- het 393b MVG CFTR SNV 7 117232223 C T R607C 0.018407 1 in 54 6.99E−05 1 in 14,314 3157 S540- het 393b MVG LRRK2 SNV 12 40657700 C G N299K 0.139067 1 in 7 2.09E−06 1 in 479,386 3192 S811- het 13a MVG LRRK2 SNV 12 40702910 C T R1398C 6.01E−05 1 in 2.09E−06 1 in 479,386 3196 S811- het 16,646 13a MVG MSH5 SNV 6 31709045 C T L85F 0.041127 1 in 24 0.000446 1 in 2,242 3139 S995- het 4a MVG MSH5 SNV 6 31729925 C T P108S 0.043373 1 in 23 0.000446 1 in 2,242 3141 S995- het 4a PML FAT4 SNV 4 126239986 C T A807V 0.490241 1 in 2 0.000273 1 in 3,665 3086 01 het PML FAT4 SNV 4 126241248 C G Q1228E 0.002227 1 in 449 0.000273 1 in 3,665 3091 01 het PML MSH5 SNV 6 31709045 C T L85F 0.041127 1 in 24 0.000310 1 in 3,224 3139 01 het PML MSH5 SNV 6 31725978 C G R188G 0.030171 1 in 33 see other see other 3140 01 het het SNVs het SNVs PML MSH5 SNV 6 31729925 C T P108S 0.043373 1 in 23 0.000327 1 in 3,057 3141 01 het PML PRRC2A SNV 6 31595926 C T P559S 0.007481 1 in 134 6.54E−05 1 in 15,280 3122 02 het PML PRRC2A SNV 6 31603045 A G D1766G 0.034995 1 in 29 6.54E−05 1 in 15,280 3133 02 het PML MSH5 SNV 6 31709045 C T L85F 0.041127 1 in 24 0.000446 1 in 2,242 3139 02 het PML MSH5 SNV 6 31729925 C T P108S 0.043373 1 in 23 0.000446 1 in 2,242 3141 02 het PML FAT4 SNV 4 126237697 A C E44A 0.000939 1 in 1,065 see other see other 3079 04 het het SNV het SNV PML FAT4 SNV 4 126240968 A T E1134D 0.004166 1 in 240 see other see other 3090 04 het het SNV het SNV PML FAT4 SNV 4 126411179 C T P2642L 0 infinite 0 infinite 3102 04 het PML C8A SNV 1 57372463 C T T407I 0.003976 1 in 252 1.15E−05 1 in 86,659 3011 05 het PML C8A SNV 1 57373778 G A D458N 0.011610 1 in 86 1.15E−05 1 in 86,659 3012 05 het PML MOGS SNV 2 74688884 G A R572W 0.006223 1 in 161 0.000581 1 in 1,720 3041 05 het PML MOGS SNV 2 74690378 C T D120N 0.373681 1 in 3 0.000581 1 in 1,720 3045 05 het PML CFTR SNV 7 117232086 G A G561D 0 infinite 0 infinite 3156 05 het PML CFTR SNV 7 117246776 T C L925P 0 infinite 0 infinite 3158 05 het PML ERCC6L2 SNV 9 98678698 G C L202F 0.001389 1 in 720 0.000115 1 in 8,675 3172 05 het PML ERCC6L2 SNV 9 98691137 T C V403A 0.331883 1 in 3 0.000115 1 in 8,675 3173 05 het PML PRRC2A SNV 6 31602967 G A R1740H 0.439204 1 in 2 0.002116 1 in 473 3132 09 het PML PRRC2A SNV 6 31605016 T C F2083S 0.019275 1 in 52 see other see other 3137 09 het het SNVs het SNVs PML PRRC2A SNV 6 31605278 C T P2130L 0.045577 1 in 22 0.000220 1 in 4,553 3138 09 het PML MSH5 SNV 6 31709045 C T L85F 0.041127 1 in 24 0.000446 1 in 2,242 3139 09 het PML MSH5 SNV 6 31729925 C T P108S 0.043373 1 in 23 0.000446 1 in 2,242 3141 09 het PML FAT4 SNV 4 126239986 C T A807V 0.490241 1 in 2 0.004647 1 in 215 3086 10 het PML FAT4 SNV 4 126412106 C G S2951C 0.037914 1 in 26 0.004647 1 in 215 3104 10 het PML PRRC2A SNV 6 31597469 A C K701Q 0.000186 1 in 5,385 1.62E−06 1 in 3124 10 het 615,476 PML PRRC2A SNV 6 31603045 A G D1766G 0.034995 1 in 29 1.62E−06 1 in 3133 10 het 615,476 PML MSH5 SNV 6 31709045 C T L85F 0.041127 1 in 24 0.000446 1 in 2,242 3139 10 het PML MSH5 SNV 6 31729925 C T P108S 0.043373 1 in 23 0.000446 1 in 2,242 3141 10 het PML SMARCAL1 SNV 2 217285060 C G P165A 0.002972 1 in 337 1.58E−05 1 in 63,333 3050 15 het PML SMARCAL1 SNV 2 217288388 G C E241Q 0.021255 1 in 47 1.58E−05 1 in 63,333 3052 15 het PML TCN2 SNV 22 31006882 T G L30R 0.000691 1 in 1,447 6.93E−06 1 in 3270 15 het 144,401 PML TCN2 SNV 22 31018975 T C L349S 0.040090 1 in 25 6.93E−06 1 in 3272 15 het 144,401 PML FAT4 SNV 4 126239986 C T A807V 0.491020 1 in 2 0.005173 1 in 193 3086 16 het PML FAT4 SNV 4 126241720 T C L1385S 0.042138 1 in 24 0.005173 1 in 193 3092 16 het PML PRRC2A SNV 6 31602967 G A R1740H 0.508843 1 in 2 0.000143 1 in 6,979 3132 16 het PML PRRC2A SNV 6 31604610 T C V2012A 0.001126 1 in 888 see other see other 3135 16 het het SNVs het SNVs PML PRRC2A SNV 6 31605016 T C F2083S 0.013115 1 in 76 3.69E−06 1 in 3137 16 het 270,779 PML PRRC2A SNV 6 31605278 C T P2130L 0.220930 1 in 5 6.22E−05 1 in 16,074 3138 16 het PML MOGS SNV 2 74689335 G T D421E 0.000817 1 in 1,223 7.83E−05 1 in 12,779 3042 19 het PML MOGS SNV 2 74690378 C T D120N 0.382905 1 in 3 7.83E−05 1 in 12,779 3045 19 het PML PLD1 SNV 3 171321023 C T V1024I 0.036230 1 in 28 0.000305 1 in 3,276 3066 20 het PML PLD1 SNV 3 171455697 G C P49A 0.033699 1 in 30 0.000305 1 in 3,276 3069 20 het PML PRRC2A SNV 6 31595795 C T P515L 0.022579 1 in 44 0.001247 1 in 802 3121 20 het PML PRRC2A SNV 6 31605278 C T P2130L 0.220930 1 in 5 0.001247 1 in 802 3138 20 het PML PRRC2A SNV 6 31601735 G A R1563Q 0.087118 1 in 11 0.009566 1 in 105 3131 21 het PML PRRC2A SNV 6 31602967 G A R1740H 0.439204 1 in 2 0.009566 1 in 105 3132 21 het PML NBAS SNV 2 15432775 C T R1518H 0.009143 1 in 109 0.000247 1 in 4,053 3033 25 het PML NBAS SNV 2 15542352 C T R1004Q 0.107957 1 in 9 0.000247 1 in 4,053 3035 25 het PML LRRK2 SNV 12 40657700 C G N299K 0.139067 1 in 7 0.004847 1 in 206 3192 27 het PML LRRK2 SNV 12 40702911 G A R1398H 0.139408 1 in 7 0.004847 1 in 206 3197 27 het PML FAT4 SNV 4 126239623 G A S686N 5.99E−05 1 in see other see other 3085 28 het 16,684 het SNVs het SNVs PML FAT4 SNV 4 126240255 A G I897V 3.00E−05 1 in 4.50E−10 1 in 3087 28 het 33,302 2,222,442,272 PML FAT4 SNV 4 126240390 A G I942V 3.00E−05 1 in 4.50E−10 1 in 3089 28 het 33,354 2,222,442,272 PML MOGS SNV 2 74690371 C T R122H 0 infinite 0 infinite 3044 30 het PML MOGS SNV 2 74690378 C T D120N 0.236303 1 in 4 see other see other 3045 30 het het SNV het SNV PML MSH5 SNV 6 31709045 C T L85F 0.041127 1 in 24 0.000446 1 in 2,242 3139 30 het PML MSH5 SNV 6 31729925 C T P108S 0.043373 1 in 23 0.000446 1 in 2,242 3141 30 het PML PRRC2A SNV 6 31593603 A G Y265C 0 infinite 0 infinite 3120 31 het PML PRRC2A SNV 6 31605278 C T P2130L 0.220930 1 in 5 see other see other 3138 31 het het SNV het SNV PML PRRC2A SNV 6 31600558 C T R1370C 3.16E−05 1 in see other see other 3128 33 het 31,613 het SNVs het SNVs PML PRRC2A SNV 6 31600696 G A G1416S 0.024081 1 in 42 1.90E−07 1 in 3129 33 het 5,251,204 PML PRRC2A SNV 6 31602967 G A R1740H 0.439204 1 in 2 3.47E−06 1 in 3132 33 het 287,912 PML PRRC2A SNV 6 31604591 C T P2006S 0.282199 1 in 4 2.23E−06 1 in 3134 33 het 448,095 PML C8A SNV 1 57333311 C A A36E 0.002695 1 in 371 0.000233 1 in 4,298 3010 36 het PML C8A SNV 1 57378149 G T R485L 0.345286 1 in 3 0.000233 1 in 4,298 3013 36 het PML FAT4 SNV 4 126238305 C A P247T 0.003905 1 in 256 0.000479 1 in 2,086 3081 36 het PML FAT4 SNV 4 126239986 C T A807V 0.491020 1 in 2 0.000479 1 in 2,086 3086 36 het PML MSH5 SNV 6 31709045 C T L85F 0.136473 1 in 7 0.007228 1 in 138 3139 36 het PML MSH5 SNV 6 31729925 C T P108S 0.211842 1 in 5 0.007228 1 in 138 3141 36 het PML MASP2 SNV 1 11090916 C A D371Y 0.306713 1 in 3 0.004783 1 in 209 3002 38 het PML MASP2 SNV 1 11106666 T C D120G 0.062380 1 in 16 0.004783 1 in 209 3005 38 het PML PRRC2A SNV 6 31597451 G A A695T 0 infinite 0 infinite 3123 38 het PML PRRC2A SNV 6 31600696 G A G1416S 0.024081 1 in 42 see other see other 3129 38 het het SNV het SNV PML RLTPR SNV 16 67680806 G A V181M 0.090170 1 in 11 0.000335 1 in 2,989 3223 38 het PML RLTPR SNV 16 67685730 A T D821V 0.014840 1 in 67 0.000335 1 in 2,989 3224 38 het PML MASP2 SNV 1 11094908 T A D355V 0.017983 1 in 56 0.000974 1 in 1,027 3003 39 het PML MASP2 SNV 1 11106648 G A P126L 0.216611 1 in 5 0.000974 1 in 1,027 3004 39 het PML FAT4 SNV 4 126239986 C T A807V 0.491020 1 in 2 0.003766 1 in 266 3086 39 het PML FAT4 SNV 4 126336851 G A V2245I 0.030677 1 in 33 0.003766 1 in 266 3096 39 het PML C8A SNV 1 57378149 G T R485L 0.161223 1 in 6 6.97E−06 1 in 143,528 3013 40 het PML C8A SNV 1 57383295 G A G554D 0.000173 1 in 5,785 6.97E−06 1 in 143,528 3014 40 het PML MSH5 SNV 6 31709045 C T L85F 0.090941 1 in 11 0.002240 1 in 446 3139 40 het PML MSH5 SNV 6 31729925 C T P108S 0.098531 1 in 10 0.002240 1 in 446 3142 40 het PML PRRC2A SNV 6 31602967 G A R1740H 0.508843 1 in 2 0.001668 1 in 599 3132 41 het PML PRRC2A SNV 6 31605016 T C F2083S 0.013115 1 in 76 see other see other 3137 41 het het SNVs het SNVs PML PRRC2A SNV 6 31605278 C T P2130L 0.220930 1 in 5 0.000724 1 in 1,381 3138 41 het PML TRAF3IP2 SNV 6 111913058 G A R78W 0.014991 1 in 67 0.000915 1 in 1,093 3144 41 het PML TRAF3IP2 SNV 6 111913262 C T D10N 0.244114 1 in 4 0.000915 1 in 1,093 3145 41 het PML PRRC2A SNV 6 31601735 G A R1563Q 0.087118 1 in 11 see other see other 3131 43 het het SNVs het SNVs PML PRRC2A SNV 6 31602967 G A R1740H 0.439204 1 in 2 0.009566 1 in 105 3132 43 het PML PRRC2A SNV 6 31604591 C T P2006S 0.282199 1 in 4 0.006146 1 in 163 3134 43 het PML LRRK2 SNV 12 40657700 C G N99K 0.139067 1 in 7 0.004847 1 in 206 3192 43 het PML LRRK2 SNV 12 40702911 G A R1398H 0.139408 1 in 7 0.004847 1 in 206 3197 43 het PML C8A SNV 1 57333311 C A A36E 0.015385 1 in 65 0.000327 1 in 3,060 3010 44 het PML C8A SNV 1 57378149 G T R485L 0.084963 1 in 12 0.000327 1 in 3,060 3013 44 het PML PLD1 SNV 3 171379953 C T R708H 3.00E−05 1 in see other see other 3067 44 het 33,309 het SNV het SNV PML PLD1 SNV 3 171431726 C G E290Q 0 infinite 0 infinite 3068 44 het PML FAT4 SNV 4 126239986 C T A807V 0.490241 1 in 2 0.005171 1 in 193 3086 44 het PML FAT4 SNV 4 126412154 G A R2967K 0.042189 1 in 24 0.005171 1 in 193 3105 44 het PML SAMD9 SNV 7 92732769 T C D881G 0.037350 1 in 27 0.001101 1 in 908 3151 46 het PML SAMD9 SNV 7 92733766 C A V549L 0.117932 1 in 8 0.001101 1 in 908 3152 46 het PML CFTR SNV 7 117230454 G C G515A 0.008531 1 in 117 2.00E−05 1 in 49,970 3155 46 het PML CFTR SNV 7 117232223 C T R607C 0.009383 1 in 107 2.00E−05 1 in 49,970 3157 46 het PML FAT4 SNV 4 126239986 C T A807V 0.490241 1 in 2 0.010840 1 in 92 3086 49 het PML FAT4 SNV 4 126373570 C T S2098F 0.088450 1 in 11 0.010840 1 in 92 3099 49 het PML PRRC2A SNV 6 31601735 G A R1563Q 0.010692 1 in 94 see other see other 3131 50 het het SNVs het SNVs PML PRRC2A SNV 6 31602967 G A R1740H 0.508843 1 in 2 0.001360 1 in 735 3132 50 het PML PRRC2A SNV 6 31604591 C T P2006S 0.324640 1 in 3 0.000868 1 in 1,152 3134 50 het PML PRRC2A SNV 6 31600696 G A G1416S 0.024081 1 in 42 see other see other 3129 51 het het SNVs het SNVs PML PRRC2A SNV 6 31602967 G A R1740H 0.439204 1 in 2 0.002644 1 in 378 3132 51 het PML PRRC2A SNV 6 31604591 C T P2006S 0.282199 1 in 4 0.001699 1 in 589 3134 51 het PML FAT4 SNV 4 126239986 C T A807V 0.490241 1 in 2 see other see other 3086 55 het het SNVs het SNVs PML FAT4 SNV 4 126412106 C G S2951C 0.037914 1 in 26 0.004647 1 in 215 3104 55 het PML FAT4 SNV 4 126412154 G A R2967K 0.042189 1 in 24 0.005171 1 in 193 3105 55 het PML SAMD9 SNV 7 92732769 T C D881G 0.046152 1 in 22 0.002109 1 in 474 3151 55 het PML SAMD9 SNV 7 92733766 C A V549L 0.182832 1 in 5 0.002109 1 in 474 3152 55 het PML FAT4 SNV 4 126239986 C T A807V 0.490241 1 in 2 0.005171 1 in 193 3086 56 het PML FAT4 SNV 4 126412154 G A R2967K 0.042189 1 in 24 0.005171 1 in 193 3105 56 het PML SAMD9 SNV 7 92732769 T C D881G 0.046152 1 in 22 0.002109 1 in 474 3151 56 het PML SAMD9 SNV 7 92733766 C A V549L 0.182832 1 in 5 0.002109 1 in 474 3152 56 het PML ITSN1 SNV 21 35122475 C T P125L 3.04E−05 1 in 1.01E−06 1 in 987,921 3256 57 het 32,871 PML ITSN1 SNV 21 35239562 A G K102R 0.133092 1 in 8 1.01E−06 1 in 987,921 3257 57 het PML MASP2 SNV 1 11090916 C A D371Y 0.359923 1 in 3 see other see other 3002 58 het het SNVs het SNVs PML MASP2 SNV 1 11106648 G A P126L 0.216611 1 in 5 see other see other 3004 58 het het SNVs het SNVs PML MASP2 SNV 1 11106673 G A R118C 0 infinite 0 infinite 3006 58 het PML SMARCAL1 SNV 2 217285104 C G S179R 0.148576 1 in 7 0.004848 1 in 206 3051 58 het PML SMARCAL1 SNV 2 217288388 G C E241Q 0.130527 1 in 8 0.004848 1 in 206 3052 58 het PML FAT4 SNV 4 126238090 G T R175L 0.001241 1 in 806 0.000152 1 in 6,565 3080 58 het PML FAT4 SNV 4 126239986 C T A807V 0.491020 1 in 2 0.000152 1 in 6,565 3086 58 het PML MOGS SNV 2 74688563 C T G679S 0.091076 1 in 11 0.008718 1 in 115 3040 59 het PML MOGS SNV 2 74690378 C T D120N 0.382905 1 in 3 0.008718 1 in 115 3045 59 het PML PEPD SNV 19 33968991 T A E106V 0.096099 1 in 10 0.001747 1 in 572 3246 59 het PML PEPD SNV 19 33980963 G A R148C 0.072732 1 in 14 0.001747 1 in 572 3247 59 het PML FAT4 SNV 4 126239241 G A V559I 0 infinite 0 infinite 3082 60 het PML FAT4 SNV 4 126411493 C T P2747S 0 infinite 0 infinite 3103 60 het PML C8A SNV 1 57372463 C T T407I 0.087199 1 in 11 0.007527 1 in 133 3011 61 het PML C8A SNV 1 57378149 G T R485L 0.345286 1 in 3 0.007527 1 in 133 3013 61 het PML C8A SNV 1 57372463 C T T407I 0.087199 1 in 11 0.007527 1 in 133 3011 63 het PML C8A SNV 1 57378149 G T R485L 0.345286 1 in 3 0.007527 1 in 133 3013 63 het PML PLD1 SNV 3 171321023 C T V1024I 0.036230 1 in 28 see other see other 3066 63 het het SNVs het SNVs PML PLD1 SNV 3 171455697 G C P49A 0.033699 1 in 30 0.000305 1 in 3,276 3069 63 het PML PLD1 SNV 3 171455739 A G F35L 0.011729 1 in 85 0.000106 1 in 9,413 3070 63 het PML PEPD SNV 19 33892731 A G I118T 0.042743 1 in 23 see other see other 3245 63 het het SNVs het SNVs PML PEPD SNV 19 33968991 T A E106V 0.096099 1 in 10 0.001027 1 in 974 3246 63 het PML PEPD SNV 19 33980963 G A R148C 0.072732 1 in 14 0.000777 1 in 1,287 3247 63 het PML FAT4 SNV 4 126239986 C T A807V 0.491020 1 in 2 0.001700 1 in 588 3086 64 het PML FAT4 SNV 4 126373570 C T S2098F 0.013846 1 in 72 0.001700 1 in 588 3099 64 het PML EGF SNV 4 110866260 G C D257H 0.042672 1 in 23 0.000480 1 in 2,084 3075 72 het PML EGF SNV 4 110897252 C G S596R 0.044974 1 in 22 0.000480 1 in 2,084 3076 72 het Table 36 lists potential cause(s) of PML in the study, un-phased potential comp het SNVs for genes in Table 31 with frequency <=1/100.

TABLE 37 Gene burden genes (same criteria as Table 13) RefSeq Ave Ave Ave Gene PML ExAC ExAC Ave Ave FET Ave Ethnicity Symbol Cases Cases Samples FET corr (270) OR Ethnicity Overlap ORC4 8 247 33171 1.51E−09 4.08E−07 29.62 EUR PRRC2A 17 729 30571 1.54E−08 4.17E−06 27.58 EUR EUR + AFR PINK1 7 315 24054 1.79E−06 4.82E−04 14.26 EUR FAT4 23 6454 32974 2.16E−05 5.84E−03 4.64 EUR EUR + AFR LRRK2 9 1431 32539 7.96E−05 2.15E−02 6.41 EUR PLD1 12 257 5158 5.87E−11 1.58E−08 25.43 AFR PRRC2A 8 52 4536 3.27E−08 8.83E−06 57.80 AFR EUR + AFR FAT4 16 1259 4867 5.64E−06 1.52E−03 9.14 AFR EUR + AFR CTC1 6 159 4730 5.64E−05 1.52E−02 11.50 AFR Table 37 lists genes in Table 31 for which the total burden of damaging variants (heterogzygous) was found to be statistically greater in PML cases versus ExAC controls. As was observed in gene burden analysis performed on the original set of 435 genes, only the category of heterozygous damaging variants yielded significant genes for the new set of 270 immune dysregulation genes.

TABLE 38 Variant burden Tier 1 SNVs (same criteria as Table 14) RefSeq PML PML PML PML PML PML PML PML PML Gene Variant Geno- EUR AFR LAT ExAC ExAC ExAC EUR EUR AFR AFR ALL ALL Symbol (hg19) type 44 21 5 EUR AFR LAT OR FET OR FET OR FET CFHR3 chr1: hom 3 3 0 57/ 41/ 16/ 36.90 0.000107 11.97 0.003235 29.76 1.250E− 196759282, 28,802 2,986 4,514 07 C > T FAT4 chr4: het 0 4 0 76/ 176/ 19/ NA NA 6.71 0.005182 9.85 0.000959 126412634, 33,339 5,194 5,784 C > G PLAU chr10: hom 0 3 0 0/ 141/ 0/ NA NA 5.98 0.019009 14.02 0.001563 75673748, 33,321 5,198 5,780 A > C MDC1 chr6: het 1 4 1 711/ 118/ 148/ 1.01 1.000000 8.91 0.001977 3.94 0.005909 30675830, 31,685 4,585 5,730 T > A MDC1 chr6: het 1 4 1 712/ 125/ 148/ 1.01 1.000000 8.39 0.002435 3.90 0.006166 30680721, 31,652 4,581 5,730 G > A RAB5B chr12: het 0 3 0 189/ 26/ 35/ NA NA 33.15 0.000192 7.89 0.007567 56385915, 33,331 5,198 5,779 GGGA > G CCBE1 chr18: het 2 3 0 768/ 21/ 83/ 2.02 0.269436 41.11 0.000107 3.84 0.012489 57103126, 33,368 5,201 5,789 G > A PLD1 chr3: het 0 3 0 101/ 188/ 20/ NA NA 4.43 0.039674 6.36 0.013380 171321023, 33,301 5,189 5,742 C > T MYSM1 chr1: het 16 7 0 7,209/ 1,248/ 645/ 2.06 0.026498 1.46 0.451989 1.87 0.017528 59131311, 33,225 4,889 5,765 G > T TCN2 chr22: het 6 0 0 1,216/ 41/ 69/ 4.14 0.005279 NA NA 3.02 0.019108 31008867, 33,109 5,144 5,776 T > C MOGS chr2: het 17 10 1 7,884/ 1,877/ 2,161/ 2.03 0.031024 1.47 0.378471 1.80 0.021224 74690378, 33,364 4,902 5,783 C > T WRAP53 chr17: het 15 8 2 6,828/ 1,712/ 1,880/ 2.00 0.037960 1.23 0.647415 1.80 0.023425 7592168, 33,192 5,136 5,783 C > G MOGS chr2: het 17 9 1 8,286/ 1,610/ 2,178/ 1.89 0.053205 1.53 0.356038 1.65 0.044663 74690039, 33,133 4,889 5,776 G > A OAS2 chr12: het 26 8 1 14,781/ 560/ 1,544/ 1.81 0.067220 5.09 0.001060 1.62 0.048285 113448288, 33,329 5,190 5,784 A > G TMC8 chr17: het 7 9 0 5,032/ 848/ 492/ 1.05 0.834739 3.80 0.004015 1.75 0.059738 76130947, 33,022 5,148 5,758 G > T NBAS chr2: hom 25 8 2 15,155/ 406/ 1,556/ 1.58 0.132924 7.27 0.000118 1.59 0.064503 15674686, 33,366 5,202 5,786 T > C NBAS chr2: hom 25 7 2 15,009/ 221/ 1,491/ 1.57 0.172287 11.11 2.070E− 1.52 0.085087 15607842, 32,894 5,133 5,637 05 T > C SERPINA1 chr14: het 6 1 0 1,942/ 81/ 253/ 2.56 0.041248 3.16 0.283151 2.05 0.092465 94847262, 33,369 5,203 5,789 T > A FAT4 chr4: het 5 0 0 1,407/ 99/ 112/ 2.91 0.037262 NA NA 2.03 0.112929 126412154, 33,350 5,192 5,785 G > A NCF4 chr22: het 17 5 0 9,101/ 522/ 1,402/ 1.68 0.092908 2.80 0.053500 1.39 0.213191 37271882, 33,366 5,202 5,788 T > C MMP9 chr20: hom 18 5 0 10,856/ 329/ 410/ 1.40 0.265273 4.25 0.012513 1.34 0.278668 44640959, 32,887 4,800 5,748 G > A CTC1 chr17: het 0 4 0 1,235/ 42/ 92/ NA NA 26.21 4.110E− 1.85 0.286669 8138569, 32,722 4,721 5,747 05 C > G OAS1 chr12: het 22 6 3 14,796/ 648/ 1,548/ 1.25 0.452928 2.81 0.039148 1.28 0.325931 113357237, 33,345 5,201 5,784 G > C OAS1 chr12: het 22 6 3 14,788/ 648/ 1,548/ 1.25 0.544210 2.81 0.039148 1.28 0.326337 113357209, 33,270 5,201 5,780 G > A CD5 chr11: hom 15 10 0 9,028/ 1,386/ 3,098/ 1.39 0.310432 2.49 0.044954 1.26 0.364341 60893235, 33,233 5,189 5,770 C > T OAS1 chr12: het 22 6 3 13,136/ 594/ 1,355/ 1.14 0.762822 2.79 0.040180 1.19 0.466504 113357442, 28,065 4,740 4,892 G > A C7 chr5: het 16 9 0 12,068/ 552/ 1,966/ 1.01 1.000000 5.91 0.000253 1.12 0.703241 40964852, 33,346 4,899 5,755 A > C SRP54 chr14: het 14 5 0 9,945/ 391/ 887/ 1.09 0.744651 3.83 0.018196 1.10 0.783330 35497285, 33,265 5,189 5,776 T > C NLRP2 chr19: het 9 0 0 2,739/ 1,241/ 1,774/ 2.84 0.009214 NA NA 0.98 1.000000 55494157, 33,004 5,094 5,706 G > A Table 38 lists top tier of variants found to be significant on the basis of variant burden analysis for genes in Table 31.

TABLE 39 Variant burden Tier 2 SNVs (same criteria as Table 15) RefSeq Gen- PML PML PML PML PML PML PML PML PML Gene Variant o- EUR AFR LAT ExAC ExAC ExAC EUR EUR AFR AFR ALL ALL Symbol (hg19) type 44 21 5 EUR AFR LAT OR FET OR FET OR FET CLPB chr11: het 0 2 1 5/ 27/ 1/ NA NA 18.39 0.006992 58.03 2.860E− 72145307, 32,307 4,744 5,748 05 C > G NOD1 chr7: het 0 2 0 3/ 1/ 1/ NA NA 540.00 4.740E− 259.18 5.180E− 30491421, 33,152 5,131 5,782 05 05 G > T MDC1 chr6: het 2 1 0 32/ 7/ 7/ 48.04 0.000986 35.47 0.033172 41.79 7.190E− 30673403, 32,318 4,973 5,692 05 A > G PLAUR chr19: het 4 0 0 295/ 8/ 41/ 11.21 0.000644 NA NA 7.75 0.002261 44153248, 33,361 5,200 5,787 T > C PLEKHM1 chr17: hom 4 1 1 735/ 8/ 52/ 4.11 0.020571 27.98 0.041216 4.72 0.002518 43555253, 30,909 4,484 5,406 A > G TFPI chr2: het 0 2 0 2/ 63/ 2/ NA NA 8.42 0.028496 19.11 0.005543 188349523, 32,880 5,103 5,620 A > G C8B chr1: het 2 2 0 408/ 18/ 31/ 3.85 0.101548 30.32 0.002800 5.82 0.006119 57409459, 33,367 5,203 5,788 C > A FAT4 chr4: het 2 0 0 74/ 3/ 7/ 21.34 0.004576 NA NA 15.34 0.008383 126241248, 33,236 4,867 5,779 C > G C9 chr5: het 2 0 0 85/ 4/ 5/ 18.63 0.005917 NA NA 13.83 0.010166 39311336, 33,334 5,201 5,770 A > T TMC8 chr17: het 2 0 0 115/ 2/ 3/ 13.67 0.010601 NA NA 10.77 0.016190 76129619, 33,116 5,174 5,778 C > T EGF chr4: het 2 0 0 109/ 2/ 10/ 14.52 0.009462 NA NA 10.73 0.016294 110929301, 33,340 5,201 5,739 T > C ATG7 chr3: het 0 2 0 48/ 47/ 27/ NA NA 11.55 0.016157 10.67 0.016487 11402163, 33,370 5,203 5,789 G > A ACD chr16: het 2 0 0 111/ 10/ 7/ 13.36 0.011075 NA NA 9.45 0.020647 67694044, 31,250 4,297 5,689 C > T ICAM1 chr19: het 2 0 0 146/ 0/ 14/ 10.65 0.016849 NA NA 7.96 0.028184 10395141, 32,810 4,915 5,732 G > A ATG5 chr6: het 3 0 0 404/ 6/ 22/ 5.94 0.016651 NA NA 4.52 0.032035 106740989, 33,200 5,111 5,751 T > C NCF2 chr1: het 3 0 0 390/ 13/ 48/ 6.19 0.014980 NA NA 4.36 0.035082 183532364, 33,366 5,203 5,787 T > A MCM5 chr22: het 3 0 0 405/ 14/ 64/ 5.96 0.016535 NA NA 4.07 0.041554 35806756, 33,370 5,203 5,789 G > A EGF chr4: het 2 0 1 20/ 506/ 25/ 79.39 0.000385 NA NA 3.56 0.057209 110865044, 33,364 5,202 5,787 G > C EGF chr4: het 2 0 1 22/ 549/ 29/ 71.98 0.000462 NA NA 3.25 0.070527 110864533, 33,276 5,149 5,777 C > T FAT4 chr4: het 0 2 0 266/ 6/ 19/ NA NA 84.72 0.000491 4.38 0.080399 126238090, 33,051 4,835 5,744 G > T EGF chr4: het 2 0 0 13/ 261/ 22/ 122.02 0.000176 NA NA 4.37 0.080707 110932508, 33,325 5,185 5,767 C > A PRRC2A chr6: het 1 2 0 610/ 60/ 102/ 1.18 0.580000 7.92 0.031896 2.39 0.139143 31605016, 31,648 4,575 5,730 T > C SAMD9 chr7: hom 0 2 0 371/ 87/ 30/ NA NA 6.08 0.050453 2.64 0.181292 92733766, 33,364 5,111 5,783 C > A RNF125 chr18: het 2 0 0 152/ 324/ 44/ 10.41 0.017592 NA NA 2.48 0.198848 29645930, 33,368 5,203 5,789 A > T Table 39 lists second tier of variants found to be significant on the basis of variant burden analysis for genes in Table 31.

TABLE 40 Summary of the subset of genes found to harbor variants of interest in the 70 PML cases (from Tables 34-39) Table 35 Table 38 Table 39 Table 34 SNV Table 36 Variant Variant Tables SNV Frequency Un-phased Burden, Burden, 34-36 Frequency (Het, Hom, SNV PML Cases PML Cases RefSeq Total Case (Het, Hom, Comp Het) Frequency Table 37 >=5 EUR 2-4 EUR Gene Level Comp Het) <=1/100 to (Comp Het) Gene and/or and/or Symbol Solutions <=1/1,000 >1/1,000 <=1/100 Burden 3 AFR 2 AFR ACD 1 1 AFR EUR ADGRL2 4 2 AFR 1 AFR, 1 EUR AIRE 3 1 EUR 2 AFR ATG5 0 EUR ATG7 3 3 EUR AFR BLK 6 1 EUR 5 EUR BRD4 1 1 EUR C3 1 1 EUR C7 1 1 EUR AFR, EUR C8A 7 1 EUR 3 AFR, 1 EUR, 2 LAT C8B 1 1 AFR AFR, EUR C9 0 EUR CAMLG 1 1 AFR CCBE1 0 AFR, EUR CCZ1 1 1 AFR CD22 1 1 AFR CD36 1 1 AFR CD37 1 1 AFR CD5 1 1 EUR CD72 1 1 LAT CFH 1 1 AFR CFHR1 1 1 LAT CFHR2 2 1 AFR, 1 LAT CFHR3 0 AFR, EUR CFHR4 1 1 AFR CFHR5 1 1 AFR CFTR 3 1 EUR, 2 LAT CHD2 1 1 AFR CLEC16A 2 1 EUR 1 AFR CLPB 0 AFR, EUR COPA 1 1 LAT CTC1 0 AFR AFR DNAJC21 1 1 EUR EGF 1 1 AFR EUR, LAT ERCC6L2 1 1 LAT FAT4 23 3 AFR, 4 AFR, 5 AFR, AFR, EUR AFR, EUR AFR, EUR 4 EUR 2 EUR 9 EUR FCER2 1 1 AFR HERC5 1 1 AFR HERC6 1 1 AFR ICAM1 1 1 AFR EUR IFI35 1 1 AFR IFIT1 1 1 EUR IFIT3 1 1 AFR IL4 1 1 EUR ITSN1 1 1 EUR 1 EUR KMT2D 6 1 AFR, 1 EUR 4 EUR KRAS 2 2 EUR LRRK2 8 1 AFR, 1 AFR, 3 EUR EUR 1 EUR 3 EUR MASP2 7 2 AFR 1 AFR, 2 AFR, 2 EUR 1 EUR MBL2 2 1 LAT 1 EUR MCM5 0 EUR MDC1 0 AFR, EUR AFR, EUR LAT MFN2 3 2 AFR 1 EUR MLH1 3 1 AFR, 1 LAT 1 EUR MMP9 2 1 AFR, AFR, EUR 1 EUR MOGS 5 1 AFR 2 AFR, AFR, EUR, 1 EUR, LAT 1 LAT MON1A 1 1 EUR MON1B 1 1 LAT MSH2 2 1 EUR, 1 LAT MSH5 9 1 EUR 1 AFR, 6 EUR, 1 LAT MX1 8 2 AFR, 1 EUR, 4 EUR 1 LAT MX2 1 1 LAT MYSM1 0 AFR, EUR NBAS 2 1 EUR 1 EUR AFR, EUR, LAT NCF1 1 1 EUR NCF2 0 EUR NCF4 0 AFR, EUR NFAT5 1 1 EUR NLRP2 0 EUR NLRX1 4 1 EUR 1 AFR, 2 LAT NOD1 2 2 LAT AFR OAS1 0 AFR, EUR, LAT OAS2 0 AFR, EUR, LAT OAS3 2 2 EUR ORC4 0 EUR PARN 1 1 EUR PEPD 2 2 AFR PINK1 0 EUR PLAU 2 2 AFR AFR PLAUR 0 EUR PLCG1 1 1 AFR PLD1 3 1 AFR 2 AFR, AFR AFR 1 EUR PLEKHM1 0 AFR, EUR, LAT PLK1 2 1 AFR, 1 EUR PLXNB1 3 1 AFR, 2 EUR PRRC2A 22 2 AFR, 2 AFR, 5 AFR, AFR, EUR AFR, EUR 6 EUR, 4 EUR, 10 EUR 1 LAT 1 LAT RAB5A 1 1 EUR RAB5B 1 1 AFR AFR RAD50 1 1 EUR RANBP2 4 1 EUR 1 AFR, 2 EUR RELA 1 1 EUR RLTPR 1 1 EUR RNF125 3 1 AFR 2 EUR EUR RPSA 1 1 EUR RSAD2 1 1 EUR SAMD9 3 2 EUR, AFR 1 LAT SAMD9L 2 1 AFR 1 AFR SERPINA1 0 AFR, EUR SERPINB2 1 1 EUR SMARCAL1 2 1 AFR, 1 LAT SMURF2 1 1 AFR SRP54 0 AFR, EUR TBC1D17 1 1 LAT TCN2 1 1 LAT EUR TEK 3 1 EUR 1 EUR, 1 LAT TFPI 0 AFR TMC8 0 AFR, EUR EUR TP53AIP1 1 1 EUR TRAF3IP2 1 1 AFR USB1 1 1 EUR USP3 1 1 EUR VEGFA 1 1 EUR WASHC5 2 1 EUR 1 EUR WRAP53 0 AFR, EUR, LAT XAF1 1 1 AFR Table 40 lists a summary of the subset of 270 genes found to harbor variants of interest in the 70 PML cases.

Example 23—Protein-Protein Interaction Analysis

This example contains analysis of protein-protein interactions (e.g., pathway analysis) for the two sets of PML candidate genes: PML-435 (Tables 6, 25A, and 25B) and PML-270 (Table 31).

An integrated list of top candidate PML genes was generated from the three analysis methods used herein: 1) case-solving approach (e.g., Tables 7-9 and 34-36); 2) gene burden analysis (e.g., Tables 13 and 37); and 3) variant burden analysis for top findings (e.g., tier 1, Tables 14 and 38) and second tier findings (e.g., tier 2, Tables 15 and 39). A gene-scoring metric was applied (see Table 42 for results) as follows: 1) case-solving, the total number of unique PML cases that are potentially solved were summed up for each gene, 2) gene burden, the number of ethnicities that were found to be significant for a given gene are reported (e.g., if AFR and EUR cases were significant in their respective analyses, then the reported number is 2), 3) variant burden (tier 1 or tier 2), the number of ethnicities that were found to be significant for a given variant are reported, and 4) gene score total, the sum of steps 1-3 (case-solving, gene burden, and variant burden) were summed up to yield the total score for a given gene wherein a higher number is a stronger candidate gene (e.g., FAT4 was the top-scoring gene with a gene score total of 29). A total of 255 genes (derived from Tables 6, 25A, 25B, and 31) were found to have variants of interest in the set of 70 PML cases for which WES and array CGH data were obtained. A gene score of >3 was set as the cutoff for pathway analysis, which yielded the 74 genes that are reported in Table 42.

Pathway analysis was performed on the set of 74 genes reported in Table 42 using the String database resource (Szklarczyk D et al. 2017, PMID 27924014). Default settings were used except for the “minimum required interaction score”, which was set to “high confidence” (the default setting is “medium confidence”).

The String database analysis yielded three main interaction networks:

-   -   1) 24-gene network (the output is depicted in FIG. 14 and         annotated in Table 42): BLK, CARD11, CFTR, EGF, IFIH1, ITSN2,         MAVS, MMP9, MX1, NFKB1, NLRX1, NOD1, NOD2, OAS1, OAS2, PIK3CD,         PLAU, PLCG2, RNF125, SAMD9, TEK, TICAM1, TLR4, ZAP70;     -   2) 13-gene network: ATM, ATR, BLM, DCLRE1C, LRRK2, MDC1, MLH1,         MSHS, POLE, PRKDC, RANBP2, RNF168, RTEL1; and     -   3) 3-gene network: C7, CBA, C8B.

TABLE 42 Analysis of Protein-Protein Interactions RefSeq Gene Variant Variant Gene Gene Source Case- Gene Burden Burden Score 24-Gene Symbol (Table) Solving Burden Tier 1 Tier 2 Total Network GO:0002250 GO:0045087 GO:0006955 GO:0002252 GO:0002253 GO:0042113 GO:0032479 GO:0030217 GO:0006958 ADGRL2 31 4 4 AIRE 31 3 3 AP3B1 6 5 1 6 ATG7 31 3 1 4 X ATM 6 8 2 10 X ATR 6 3 1 4 BLK 31 6 6 X X X X X BLM 6 2 1 3 X C7 31 1 2 3 X X X X X X C8A 31 7 7 X X X X X X C8B 31 1 2 3 X X X X X X CARD11 6 3 3 X X X X X CFTR 31 3 3 X CHD7 6 4 1 1 6 X DCLRE1C 6 10 10 X DOCK8 25A, 11 2 13 25B EGF 31 1 2 3 X X X EPG5 6 12 1 13 FAT4 31 23 2 2 2 29 GFI1 6 4 2 6 HIVEP1 6 6 1 7 HIVEP2 6 2 2 4 HIVEP3 6 3 3 IDO2 6 5 5 IFIH1 6 3 3 6 X X X X X X IGLL1 6 3 2 5 X ITSN2 6 2 2 4 X KMT2D 31 6 6 LRBA 6 1 1 2 4 LRRK2 31 8 1 9 LYST 6 4 1 1 6 X X MASP2 31 7 7 X X X X X X MAVS 6 2 2 4 X X X X X MDC1 31 3 2 5 MFN2 31 3 3 MLH1 31 3 3 X X X X MMP9 31 2 2 4 X MOGS 31 5 3 8 MSH5 31 9 9 MX1 31 8 8 X X X X NBAS 31 2 3 5 NFKB1 6 3 3 X X X X X NLRX1 31 4 4 X X X NOD1 31 2 1 3 X X X X NOD2 6 6 1 7 X X X X X OAS1 31 3 3 X X X X OAS2 31 3 3 X X X X PIK3CD 6 4 1 5 X X X X X X X X PKHD1 6 11 11 PLAU 31 2 1 3 X PLCG2 6 5 2 2 9 X X X X PLD1 31 3 1 1 5 PLEKHM1 31 3 3 PLXNB1 31 3 3 POLE 6 7 2 9 PRKDC 6 4 4 X X X X X PRRC2A 31 22 2 2 26 RAG1 25A, 4 4 X X X 25B RANBP2 31 4 4 RBFOX1 6 2 1 3 RNF125 31 3 1 4 X X X X RNF168 6 5 5 X X X X RTEL1 6 2 1 3 SAMD9 31 3 1 4 X SHARPIN 6 2 1 2 1 6 SKIV2L 6 3 3 STXBP2 6 3 1 4 X X TEK 31 3 3 X TICAM1 6 2 1 3 X X X X X TLR4 6 9 9 X X X X X X X X TNFRSF11A 6 10 10 X X TRPM2 6 5 5 WRAP53 31 3 3 ZAP70 6 3 3 X X X X X X

Table 42 contains the gene scoring results, genes found in the 24-gene network, plus the top 5 “Biological Process” gene ontology (GO) pathways (based on the “false discovery rate” values reported in the String db output) and representative additional GO pathways of interest. Column headings and GO results are reported below:

RefSeq Gene Symbol, reports genes from Tables 6, 25A, 25B, and 31 that had a “Gene Score Total” of >=3.

Gene Source, reports the original source table(s) of immune dysregulation genes.

Case-Solving, reports the total number unique PML cases that are potentially solved using the case-solving approach (described herein for Tables 7-9 and 34-36).

Gene Burden, reports the number of ethnicities (AFR, EUR, and/or LAT) that were found with the gene burden method (described herein for Tables 13 and 37).

Variant Burden Tier 1, reports the number of ethnicities (AFR, EUR, and/or LAT) that were found with the variant burden method (described herein for Tables 14 and 38).

Variant Burden Tier 2, reports the number of ethnicities (AFR, EUR, and/or LAT) that were found with the variant burden method (described herein for Tables 15 and 39).

Gene Score Total, reports the sum of Case-Solving, Gene Burden, Variant Burden Tier 1, and Variant Burden Tier 2 entries (described herein), wherein only genes with a score of >=3 were included.

24-Gene Network, identifies the genes (marked with an X) found in the largest network from the String db analysis (described herein), see FIG. 14 for a graphical depiction.

The next 9 column headings list the “pathway ID” GO identifier numbers and identify the genes (marked with an X) that were found in each pathway from the total set of 74 genes in Table 42. Also listed below is the GO “pathway description”, the “count in gene set” (number of genes from Table 42), and the “false discovery rate” (association value):

GO:0002250, adaptive immune response, 13 genes, 1.12e-10

GO:0045087, innate immune response, 23 genes, 1.35e-10

GO:0006955, immune response, 26 genes, 1.54e-10

GO:0002252, immune effector process, 16 genes, 2.70e-09

GO:0002253, activation of immune response, 16 genes, 2.70e-09

GO:0042113, B cell activation, 9 genes, 5.24e-07

GO:0032479, regulation of type I interferon production, 8 genes, 3.70e-06

GO:0030217, T cell differentiation, 7 genes, 6.65e-05

GO:0006958, complement activation, classical pathway, 4 genes, 6.10e-04

Example 24—Analysis of Deleterious/Protective Variants

The WES data on the 70 PML cases were also analyzed for variants that occur at a statistically significant rate among the 705 total (435 from the original analysis and 270 from the second analysis) genes that have herein been identified as playing a role in immune dysregulation. In this analysis, “statistically significant” can be having an FET P-Value, after Bonferroni correction, of P<4.95E⁻⁶. Inclusion criteria included any SNV showing statistical significance at in one or more ethnic group (European, African or Latino) or across all groups. Some of these variants may occur with high frequency among the 70 PML cases. Some of these variants may occur in patients with HIV, MS, or other diseases as described herein, or any combination thereof. Observation of these variants in the 70 PML cases suggests that there may be a link between these variants and PML. Table 43 lists statistically significant deleterious variants (such as variant 18-60052034-A-C, SEQ ID No. 1287), observed in the 70 PML cases with WES data. Table 44 lists statistically significant protective variants observed in the 70 PML cases with WES data. Column headers: Variant; Gene; Total PML; Ethnicities; Diseases; FET P-Values: EUR; FET P-Values: AFR; FET P-Values: LAT; FET P-Values: ALL; Odds Ratios: EUR; Odds Ratios: AFR; Odds Ratios: LAT; Odds Ratios: ALL.

TABLE 43 Summary of statistically significant deleterious variants that have been observed in the 70 PML cases with WES data PML FET P-Values Odds Ratios Variant Gene Total Ethnicities Diseases EUR AFR LAT All EUR AFR LAT All 1-154600405-T-C ADAR 69 3 3 1.2E−28 2.3E−34 7.0E−09 1.4E−53 165.6 Inf Inf 359.5 1-154600394-T-C ADAR 4 2 1 2.4E−02 1.2E−07 1.0E+00 1.4E−09 45.1 Inf 0.0 352.0 1-154600411-A-C ADAR 65 3 3 1.7E−29 1.0E−35 9.7E−08 4.7E−53 72.3 1510.3 344.0 93.3 1-33476387-C-T AK2 70 3 3 1.6E−16 3.5E−07 8.4E−03 7.4E−26 Inf Inf Inf Inf 1-33476385-C-G AK2 70 3 3 6.4E−16 9.5E−07 1.1E−02 7.3E−25 Inf Inf Inf Inf 1-33476353-C-T AK2 70 3 3 6.7E−07 2.1E−03 1.7E−01 8.0E−11 Inf Inf Inf Inf 1-33476435-C-A AK2 40 3 2 2.7E−82 2.0E−25 3.6E−10  6.9E−118 Inf Inf Inf Inf 1-33475721-G-C AK2 67 3 3 2.1E−11 1.5E−06 5.2E−02 7.0E−18 22.9 29.8 Inf 25.0 1-33476404-T-G AK2 64 3 3 2.9E−14 1.6E−07 4.0E−02 2.4E−22 18.1 29.9 8.5 19.2 1-33476396-G-A AK2 64 3 3 7.9E−14 2.5E−07 4.3E−02 1.2E−21 17.4 28.8 8.2 18.5 1-33475687-C-G AK2 49 3 3 9.8E−15 2.2E−04 2.0E−02 6.9E−18 12.7 6.5 12.3 9.0 1-33476143-G-A AK2 24 3 3 9.9E−08 6.9E−02 6.0E−02 2.3E−08 6.6 3.5 10.7 5.2 19-2129067-A-G AP3D1 21 3 3 2.0E−25 8.2E−13 3.5E−02 2.7E−39 Inf Inf Inf Inf 22-39357634-A-G APOBEC3A 16 3 2 9.2E−09 4.5E−06 2.7E−02 5.9E−18 31.9 12.0 46.4 31.9 22-39358241-C-T APOBEC3A 17 3 2 1.0E−07 1.2E−02 8.2E−06 7.1E−12 10.2 7.0 162.2 11.3 11-108114883-T-C ATM 9 2 1 1.0E+00 2.4E−01 4.0E−06 1.8E−05 0.0 1.9 208.8 6.8 6-31997129-G-C C4B 26 2 3 3.1E−08 4.1E−04 6.0E−01 4.4E−08 6.2 7.8 0.0 4.4 11-60891305-A-C CD5 31 3 3 3.7E−51 3.0E−20 1.1E−05 2.1E−76 4176.5 Inf 1278.4 4457.8 1-160519815-C-CT CD84 31 3 3 4.8E−06 1.6E−02 1.3E−03 1.2E−10 4.6 3.0 27.4 5.3 2-174229756-A-G CDCA7 3 1 2 3.6E−06 1.6E−01 1.0E+00 8.5E−02 124.7 0.0 0.0 3.0 14-23588326-G-C CEBPE 17 3 2 1.4E−25 3.8E−09 5.2E−03 1.8E−37 Inf Inf Inf Inf 14-23588316-T-C CEBPE 9 2 2 2.9E−15 1.5E−05 1.0E+00 7.1E−20 Inf 199.6 0.0 1010.1 1-196642969-CT-C CFH 2 1 1 1.0E+00 1.0E+00 3.8E−06 3.3E−02 0.0 0.0 1726.0 7.2 1-196797357-A-G CFHR1 37 3 3 3.4E−10 3.0E−02 1.0E+00 7.2E−12 7.2 2.6 1.2 5.5 16-88710039-T-C CYBA 5 2 1 3.2E−02 4.0E−04 1.0E+00 1.5E−07 Inf Inf 0.0 Inf 1-161518336-C-T FCGR3A 30 3 3 1.6E−06 2.8E−03 6.5E−01 2.2E−06 4.7 4.1 0.4 3.4 4-89400457-C-A HERC5 6 2 1 3.4E−08 4.1E−05 1.0E+00 6.0E−12 167.2 Inf 0.0 195.2 4-89400460-T-A HERC5 6 2 1 1.8E−06 3.3E−04 1.0E+00 6.8E−09 55.9 197.4 0.0 52.3 1-42049542-G-A HIVEP3 6 2 1 1.0E+00 1.0E+00 3.0E−06 2.3E−03 0.0 0.9 228.1 4.8 1-42050364-G-T HIVEP3 6 2 1 1.0E+00 1.0E+00 2.9E−06 2.5E−03 0.0 0.9 234.9 4.7 21-45650009-T-TG ICOSLG 19 3 3 2.8E−17 3.8E−14 1.4E−03 1.2E−34 Inf Inf Inf Inf 21-45649595-T-C ICOSLG 9 2 2 2.6E−06 2.5E−03 1.0E+00 1.1E−08 23.1 Inf 0.0 24.2 21-45649580-A-G ICOSLG 9 2 2 2.2E−06 1.9E−02 1.0E+00 2.7E−07 16.7 Inf 0.0 14.6 10-1061646-T-C IDI2 39 3 3 2.5E−67 1.1E−21 3.1E−03 4.0E−93 Inf Inf Inf Inf 10-1061650-C-G IDI2 40 3 3 6.5E−67 2.6E−20 8.1E−06 1.0E−94 Inf Inf Inf Inf 8-42128955-A-G IKBKB 5 2 3 2.5E−06 3.6E−01 1.0E+00 3.1E−06 Inf 4.2 0.0 87.4 5-78610478-A-C JMY 10 3 1 8.4E−14 2.2E−07 2.4E−03 1.5E−22 468.4 Inf 910.6 581.7 5-78610472-T-C JMY 12 3 3 5.4E−11 2.2E−09 1.6E−06 6.5E−23 127.6 Inf Inf 225.3 19-48613788-T-G LIG1 35 3 3 1.5E−31 1.9E−21 6.6E−05 8.3E−59 Inf 261.6 169.8 590.8 21-42775180-C-CT MX2 9 2 2 3.7E−18 5.9E−08 1.0E+00 3.7E−26 Inf Inf 0.0 Inf 11-119050352-T-C NLRX1 3 2 2 1.8E−06 4.2E−03 1.0E+00 4.2E−09 Inf Inf 0 Inf 11-119044844-C-T NLRX1 4 2 1 2.0E−06 1.5E−01 1.0E+00 6.0E−02 154.9 0.2 0.0 2.8 11-119044158-C-T NLRX1 4 2 1 1.6E−06 2.4E−01 1.0E+00 6.5E−02 166.3 0.2 0.0 2.8 11-119045300-T-G NLRX1 5 2 1 4.2E−06 2.0E−01 1.0E+00 4.8E−02 115.8 0.3 0.0 2.6 11-119045431-T-C NLRX1 4 2 1 1.4E−06 1.5E−01 1.0E+00 7.8E−02 173.4 0.2 0.0 2.6 6-51503623-T-A PKHD1 21 3 3 2.9E−03 5.7E−08 1.6E−01 5.2E−06 2.8 28.4 7.2 3.7 17-43552812-A-G PLEKHM1 21 3 3 2.5E−09 2.5E−06 9.1E−02 5.3E−14 10.4 20.5 13.0 11.3 22-37622880-G-GT RAC2 22 3 3 5.0E−24 6.6E−01 4.4E−05 4.3E−12 283.4 0.7 90.6 8.4 8-145154824-A-C SHARPIN 3 1 1 2.7E−08 1.0E+00 1.0E+00 4.9E−08 1082.8 0.0 0.0 892.3 11-62655878-C-T SLC3A2 7 2 1 1.0E+00 5.4E−01 1.0E−06 3.4E−04 0.0 1.3 336.4 5.8 19-50394219-G-C TBC1D17 20 3 3 1.7E−14 1.3E−05 4.1E−02 1.2E−20 36.4 19.2 41.4 33.0 18-60052034-A-C TNFRSF11A 9 2 1 1.4E−20 2.4E−05 1.0E+00 1.7E−25 Inf Inf 0.0 Inf

TABLE 44 Summary of statistically significant protective variants that have been observed in the 70 PML cases with WES data PML FET P-Values Odds Ratios Variant Gene Total Ethnicities Diseases EUR AFR LAT All EUR AFR LAT All 1-154562624-CG-C ADAR 7 2 3 1.2E−37 3.8E−13 5.9E−08 2.6E−60 0.0 0.0 0.0 0.0 1-154562625-G-C ADAR 4 1 1  2.5E−120 1.3E−34 3.7E−14  3.1E−168 0.0 0.0 0.0 0.0 1-33476223-TAC-T AK2 58 3 3 1.0E−04 3.7E−04 2.1E−01 1.8E−08 0.1 0.1 0.2 0.1 1-33475967-G-A AK2 41 3 3 9.6E−20 3.1E−05 2.3E−02 2.2E−28 0.0 0.1 0.0 0.0 1-33478931-G-C AK2 1 1 1 8.9E−24 1.0E−08 1.5E−03 5.9E−35 0.0 0.0 0.0 0.0 1-33475982-C-A AK2 4 2 1 8.6E−46 3.8E−10 8.9E−06 1.1E−63 0.0 0.0 0.0 0.0 1-33478959-C-G AK2 1 1 1 8.6E−37 3.8E−13 1.2E−05 1.9E−55 0.0 0.0 0.0 0.0 9-100756891-C-CT ANP32B 12 3 3 6.0E−18 2.0E−07 1.7E−01 7.7E−23 0.1 0.1 0.2 0.1 19-2129473-T-C AP3D1 3 2 1 3.1E−18 4.0E−03 3.8E−01 3.9E−23 0.0 0.0 0.3 0.0 19-2129474-C-G AP3D1 3 1 2 8.2E−17 4.0E−03 6.3E−02 3.6E−23 0.0 0.0 0.0 0.0 22-39387655-G-T APOBEC3B 20 3 3 1.2E−10 6.5E−03 2.1E−02 5.4E−16 0.1 0.3 0.1 0.1 9-119491277-C-T ASTN2 2 2 1 1.0E−09 1.0E+00 1.0E+00 1.3E−09 0.0 0.7 0.0 0.1 5-115167595-CT-C ATG12 17 2 3 9.2E−15 3.8E−11 1.7E−06 5.6E−22 0.1 0.0 0.0 0.1 3-142231081-G-A ATR 8 3 2 9.9E−20 5.5E−15 5.9E−07 7.6E−34 0.0 0.0 0.0 0.0 6-31994974-G-A C4B 8 2 2 8.3E−02 1.1E−06 3.4E−01 3.5E−04 0.5 0.1 0.0 0.3 6-31994782-C-T C4B 7 3 3 4.5E−06 5.0E−01 5.3E−01 1.9E−06 0.2 0.4 1.5 0.2 6-31997401-G-A C4B 8 2 3 1.2E−06 7.1E−01 4.3E−03 2.0E−11 0.2 0.5 0.0 0.1 6-31997321-C-T C4B 19 3 3 8.4E−21 1.2E−03 5.9E−02 1.9E−25 0.0 0.2 0.1 0.1 6-31994750-T-C C4B 3 2 1 2.3E−05 6.0E−07 5.2E−03 3.4E−11 0.1 0.1 0.0 0.1 6-31994742-A-G C4B 3 2 1 2.3E−05 6.8E−07 4.7E−03 3.1E−11 0.1 0.1 0.0 0.1 6-31997600-C-G C4B 27 3 3 4.8E−16 2.6E−06 2.7E−05 9.4E−27 0.1 0.1 0.0 0.1 6-31994723-G-A C4B 3 1 2 5.3E−09 1.6E−01 1.4E−03 7.1E−15 0.1 0.0 0.0 0.1 9-123762321-G-A C5 12 2 3 5.7E−11 7.1E−02 7.9E−03 6.2E−17 0.1 0.2 0.0 0.1 2-87012399-TA-T CD8A 1 1 1 1.6E−11 1.4E−04 1.4E−01 4.9E−18 0.0 0.0 0.0 0.0 2-174230974-G-T CDCA7 15 3 2 8.5E−37 3.7E−01 2.9E−05 9.0E−34 0.0 0.6 0.0 0.0 20-48808011-C-T CEBPB 41 3 3 2.4E−07 2.4E−01 5.1E−02 2.6E−10 0.2 0.6 0.1 0.2 22-42343091-G-A CENPM 36 3 3 7.6E−01 1.9E−06 5.6E−01 1.0E+00 1.1 0.1 0.7 1.0 16-1493491-T-G CLCN7 33 3 3 1.3E−07 1.0E+00 3.8E−03 4.2E−06 0.2 1.1 0.0 0.3 13-40252190-C-T COG6 25 3 3 4.7E−06 3.5E−01 1.6E−01 1.8E−07 0.2 0.6 0.3 0.3 13-40326284-CA-C COG6 22 3 3 7.9E−11 7.7E−05 3.0E−02 1.8E−18 0.1 0.1 0.1 0.1 9-399275-A-AC DOCK8 20 3 3 1.0E+00 2.3E−06 3.8E−01 2.1E−02 1.0 0.1 0.3 0.5 12-93247775-G-GATA EEA1 47 3 3 5.8E−02 4.5E−01 4.2E−06 1.6E−04 0.5 0.7 0.0 0.4 5-137847084- ETF1 3 3 1 2.8E−09 8.0E−05 6.5E−01 1.7E−12 0.0 0.1 0.4 0.1 CACACACAT-C 5-137847090-CAT-C ETF1 2 2 1 5.3E−12 3.8E−03 1.8E−01 4.3E−16 0.0 0.1 0.0 0.0 12-11903753-C-T ETV6 2 2 1 1.0E+00 4.2E−12 4.3E−02 2.0E−03 0.0 0.0 0.1 0.2 12-11903752-G-T ETV6 2 2 1 1.0E+00 2.6E−15 3.0E−02 5.7E−04 0.0 0.0 0.1 0.1 12-11903751-TGC-T ETV6 1 1 1 8.9E−14 7.6E−15 4.9E−04 1.0E−26 0.0 0.0 0.0 0.0 8-39842443-C-CTTAT IDO2 12 2 2 3.2E−10 3.3E−02 9.6E−03 1.4E−14 0.1 0.3 0.0 0.1 22-17590180-G-A IL17RA 19 3 2 1.3E−11 6.9E−04 4.0E−01 2.2E−11 0.1 0.2 3.0 0.2 1-82402364-TAATC-T LPHN2 10 3 3 5.3E−10 2.4E−02 1.0E+00 1.7E−11 0.1 0.3 0.6 0.1 6-74161762-G-T MB21D1 3 2 2 7.3E−07 1.4E−01 5.9E−01 8.8E−07 0.0 3.6 0.0 0.1 21-42775180-C-T MX2 30 3 3 4.2E−38 7.8E−18 1.1E−10 1.5E−62 0.0 0.0 0.0 0.0 1-59150941-G-A MYSM1 54 3 3 9.6E−13 1.5E−05 1.0E+00 2.5E−16 0.0 0.0 Inf 0.0 7-74197598-T-A NCF1 5 2 2 3.0E−26 2.1E−01 4.8E−04 2.3E−27 0.0 0.4 0.0 0.0 22-37268257-C-T NCF4 52 3 3 5.7E−07 1.0E+00 1.5E−01 5.2E−07 0.1 0.9 0.1 0.2 11-119050352-T- NLRX1 2 2 1 2.5E−02 6.6E−07 1.0E+00 2.4E−04 0.2 0.0 0.0 0.1 TGAACAGGCA CATGGAAGGCC 12-113376543- OAS3 29 3 3 2.2E−09 1.7E−18 5.3E−03 2.7E−17 0.2 0.0 0.1 0.1 C-CCAAAGGG 1-9714543-A-ACCCC PIK3CD 18 3 3 2.3E−09 1.2E−09 5.7E−03 5.2E−12 0.1 0.0 0.1 0.2 1-9714544-A-AG PIK3CD 18 3 3 1.7E−09 1.8E−12 4.8E−03 2.7E−12 0.1 0.0 0.1 0.2 1-9714541-C-CCA PIK3CD 18 3 3 1.7E−09 3.6E−12 4.5E−03 2.3E−12 0.1 0.0 0.1 0.2 12-133195625-G-A POLE 56 3 3 6.2E−12 2.7E−03 1.7E−02 1.2E−15 0.0 0.1 0.0 0.0 3-53223286- PRKCD 12 2 2 4.6E−21 1.2E−08 1.7E−01 1.1E−27 0.0 0.1 0.0 0.1 GCTGGT-G 3-53223291-T-G PRKCD 57 3 3 1.0E−20 1.7E−03 1.0E+00 6.3E−18 0.0 0.1 Inf 0.0 2-128181234-GC-G PROC 10 3 2 1.1E−09 1.7E−02 1.0E+00 1.7E−11 0.0 0.0 0.0 0.0 12-56380689-T-C RAB5B 6 3 2 8.7E−18 1.5E−06 8.7E−03 2.5E−24 0.0 0.1 0.1 0.0 11-62638333-T-A SLC3A2 12 3 3 3.1E−06 1.5E−01 1.0E+00 3.9E−09 0.2 0.2 1.0 0.2 11-62638330-T-A SLC3A2 15 3 3 1.1E−09 3.3E−02 1.0E+00 7.2E−14 0.1 0.1 0.7 0.1 11-62638200-T-A SLC3A2 3 2 1 6.9E−08 4.9E−03 1.7E−01 3.0E−11 0.0 0.0 0.0 0.0 5-147504315-A-T SPINK5 41 3 3 1.9E−18 5.1E−07 4.3E−02 1.0E−24 0.0 0.0 0.0 0.0 4-26862782-C-G STIM2 19 3 3 9.1E−10 6.1E−03 3.4E−03 4.5E−17 0.1 0.2 0.0 0.1 4-26862754-C-T STIM2 18 3 3 1.2E−18 2.8E−07 2.8E−04 1.9E−32 0.1 0.1 0.0 0.0 19-7705236-C-CTG STXBP2 34 3 3 5.4E−01 7.7E−08 3.6E−01 8.1E−02 0.8 0.1 3.6 0.6 19-50394205-T-C TBC1D17 1 1 1 2.1E−08 4.4E−05 1.0E+00 3.9E−13 0.0 0.0 0.0 0.0 22-19754091-A-C TBX1 16 2 2 1.7E−07 7.6E−01 6.5E−05 7.9E−13 0.2 1.2 0.0 0.2 2-47277208-A-G TTC7A 2 2 1 1.4E−17 1.3E−23 2.7E−04 8.6E−32 0.0 0.0 0.0 0.0 9-132640726-T-G USP20 24 3 3 5.0E−06 1.0E+00 6.8E−01 2.2E−07 0.2 1.0 0.6 0.3 9-132632162-G-GC USP20 53 3 3 3.3E−12 3.0E−02 1.0E−04 1.3E−15 0.0 0.3 0.0 0.1 11-9595768-C-T WEE1 13 3 3 1.7E−07 9.0E−05 5.8E−01 5.9E−11 0.1 0.1 0.5 0.1

Example 25—Description of Further Sequence Data

The sequence file 56969-701.601 ST25.txt contains genomic information for:

1. The genetic sequence information referenced in Example 4 (SEQ IDs 1-2177); 2. SEQ ID 2200-2203 are the distinct CNV sequences for the CNVs in Table 28A; 3. SEQ ID 2204-2215 are the full genomic extent of the transcript sequences for the transcripts in Table 30; 4. SEQ ID 2300-2893 are the full genomic extent of the transcript sequences for the transcripts in Table 32; 5. SEQ ID 3000-3274 are the sequence variants listed in Table 33; 6. SEQ ID 3275-3281 are the full genomic extent of the transcript sequences for the transcripts in Table 49; 7. SEQ ID 3300-3351 are the sequence variants listed in Table 45A; 8. SEQ ID 3400-3467 are the sequence variants listed in Table 45B; 9. SEQ ID 3500-3526 are the sequence variants listed in Table 45C.

TABLE 45A SEQ ID 3300-3351, SNV list (Table 43) with SEQ ID numbers Chromosome Position (hg19) Ref Allele Alt Allele SEQ ID 1 33475687 C G 3310 1 33475721 G C 3307 1 33476143 G A 3311 1 33476353 C T 3305 1 33476385 C G 3304 1 33476387 C T 3303 1 33476396 G A 3309 1 33476404 T G 3308 1 33476435 C A 3306 1 42049542 G A 3328 1 42050364 G T 3329 1 154600394 T C 3301 1 154600405 T C 3300 1 154600411 A C 3302 1 160519815 C CT 3318 1 161518336 C T 3325 1 196642969 CT C 3322 1 196797357 A G 3323 2 174229756 A G 3319 4 89400457 C A 3326 4 89400460 T A 3327 5 78610472 T C 3337 5 78610478 A C 3336 6 31997129 G C 3316 6 51503623 T A 3345 8 42128955 A G 3335 8 145154824 A C 3348 10 1061646 T C 3333 10 1061650 C G 3334 11 60891305 A C 3317 11 62655878 C T 3349 11 108114883 T C 3315 11 119044158 C T 3342 11 119044844 C T 3341 11 119045300 T G 3343 11 119045431 T C 3344 11 119050352 T C 3340 14 23588316 T C 3321 14 23588326 G C 3320 16 88710039 T C 3324 17 43552812 A G 3346 18 60052034 A C 3351 19 2129067 A G 3312 19 48613788 T G 3338 19 50394219 G C 3350 21 42775180 C CT 3339 21 45649580 A G 3332 21 45649595 T C 3331 21 45650009 T TG 3330 22 37622880 G GT 3347 22 39357634 A G 3313 22 39358241 C T 3314

TABLE 45B SEQ ID 3400-3467, SNV list (Table 44) with SEQ ID numbers Chromo- Position Ref Alt SEQ some (hg19) Allele Allele ID 1 9714541 C CCA 3449 1 9714543 A ACCCC 3447 1 9714544 A AG 3448 1 33475967 G A 3403 1 33475982 C A 3405 1 33476223 TAC T 3402 1 33478931 G C 3404 1 33478959 C G 3406 1 59150941 G A 3442 1 82402364 TAATC T 3439 1 154562624 CG C 3400 1 154562625 G C 3401 2 47277208 A G 3464 2 87012399 TA T 3423 2 128181234 GC G 3453 2 174230974 G T 3424 3 53223286 GCTGGT G 3451 3 53223291 T G 3452 3 142231081 G A 3413 4 26862754 C T 3460 4 26862782 C G 3459 5 115167595 CT C 3412 5 137847084 CACACACAT C 3432 5 137847090 CAT C 3433 5 147504315 A T 3458 6 31994723 G A 3421 6 31994742 A G 3419 6 31994750 T C 3418 6 31994782 C T 3415 6 31994974 G A 3414 6 31997321 C T 3417 6 31997401 G A 3416 6 31997600 C G 3420 6 74161762 G T 3440 7 74197598 T A 3443 8 39842443 C CTTAT 3437 9 399275 A AC 3430 9 100756891 C CT 3407 9 119491277 C T 3411 9 123762321 G A 3422 9 132632162 G GC 3466 9 132640726 T G 3465 11 9595768 C T 3467 11 62638200 T A 3457 11 62638330 T A 3456 11 62638333 T A 3455 11 119050352 T TGAACAGGCACATG 3445 GAAGGCC 12 11903751 TGC T 3436 12 11903752 G T 3435 12 11903753 C T 3434 12 56380689 T C 3454 12 93247775 G GATA 3431 12 113376543 C CCAAAGGG 3446 12 133195625 G A 3450 13 40252190 C T 3428 13 40326284 CA C 3429 16 1493491 T G 3427 19 2129473 T C 3408 19 2129474 C G 3409 19 7705236 C CTG 3461 19 50394205 T C 3462 20 48808011 C T 3425 21 42775180 C T 3441 22 17590180 G A 3438 22 19754091 A C 3463 22 37268257 C T 3444 22 39387655 G T 3410 22 42343091 G A 3426

TABLE 45C SEQ ID 3500-3526, SNV list (Table 50A) with SEQ ID numbers Chromo- Position Ref Alt SEQ some (hg19) Allele Allele ID 1 27699670 AG A 3500 1 42047208 C G 3501 1 57409459 C A 3502 1 92946625 G C 3503 1 160769595 AG A 3504 1 196918605 A G 3505 2 163136505 C G 3506 2 230579019 G A 3507 3 58191230 G T 3508 4 151793903 T C 3509 6 3015818 G A 3510 6 30673359 T G 3511 6 32814942 C T 3512 6 32816772 C A 3513 6 51798908 C T 3514 9 137779251 G A 3515 11 67818269 G A 3516 11 108106443 T A 3517 14 94847262 T A 3518 16 81942175 A G 3519 19 7712287 G C 3520 19 8564523 T G 3521 19 48643270 C T 3522 21 45708278 G A 3523 22 23915583 T C 3524 22 23915745 G A 3525 22 35806756 G A 3526

TABLE 48 GN 763-765, NCBI Gene ID, descriptions, RefSeq summary for 3 genes from all-genes variant burden analyses (Table 50A) RefSeq NCBI Gene Gene Gene Gene No. Symbol ID Description RefSeq Summmary (GN) FCN2 2220 ficolin-2 The product of this gene belongs 763 isoform a to the ficolin family of proteins. precursor This family is characterized by the presence of a leader peptide, a short N-terminal segment, followed by a collagen-like region, and a C- terminal fibrinogen-like domain. This gene is predominantly expressed in the liver, and has been shown to have carbohydrate binding and opsonic activities. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul. 2008]. LY9 4063 T-lymphocyte LY9 belongs to the SLAM family 764 surface antigen of immunomodulatory receptors Ly-9 isoform a (see SLAMF1; MIM 603492) and precursor interacts with the adaptor molecule SAP (SH2D1A; MIM 300490) (Graham et al., 2006 [PubMed 16365421]). [supplied by OMIM, Mar. 2008]. PRAM1 84106 PML-RARA- The protein encoded by this gene is 765 regulated similar to FYN binding protein adapter (FYB/SLAP-130), an adaptor molecule 1 protein involved in T cell receptor mediated signaling. This gene is expressed and regulated during normal myelopoiesis. The expression of this gene is induced by retinoic acid and is inhibited by the expression of PML-RARalpha, a fusion protein of promyelocytic leukemia (PML) and the retinoic acid receptor-alpha (RARalpha). [provided by RefSeq, Jul. 2008].

TABLE 49 SEQ ID 3275-3281, non-redundant list of transcript variants that correspond to the genes in Table 48 RefSeq RefSeq Gene Accession SEQ Symbol Number mRNA Description ID LY9 NM 001033667 Homo sapiens lymphocyte antigen 3275 9 (LY9), transcript variant 2, mRNA. LY9 NM 001261456 Homo sapiens lymphocyte antigen 3276 9 (LY9), transcript variant 3, mRNA. LY9 NM 001261457 Homo sapiens lymphocyte antigen 3277 9 (LY9), transcript variant 4, mRNA. LY9 NM 002348 Homo sapiens lymphocyte antigen 3278 9 (LY9), transcript variant 1, mRNA. FCN2 NM 004108 Homo sapiens ficolin (collagen/ 3279 fibrinogen domain containing lectin) 2 (hucolin) (FCN2), transcript variant SV0, mRNA. FCN2 NM 015837 Homo sapiens ficolin (collagen/ 3280 fibrinogen domain containing lectin) 2 (hucolin) (FCN2), transcript variant SV1, mRNA. PRAM1 NM 032152 Homo sapiens PML-RARA 3281 regulated adaptor molecule 1 (PRAM1), mRNA.

Example 26—PML Discovery and Replication Cohorts

The cohort of 70 PML cases whose analysis was described previously (e.g., the genetic results reported in Table 7) can be considered a ‘Discovery’ (Dis) cohort. An additional study was performed on a ‘Replication’ (Rep) cohort comprising 115 additional PML cases. These 115 cases were obtained from 4 different sources, only one of which was the same as one of the sources for the Dis cohort. Table 46 lists information for all 185 PML cases (Dis cohort=70 cases, Rep cohort=115 cases). As was done for the Dis PML cohort (Example 3), WES data was obtained on the 115 Rep PML cases. Unlike the Dis cohort, aCGH was not performed on the Rep cohort. However, those skilled in the art know that CNVs (e.g., those reported in Tables 1 and 28A) can be detected by other methods besides aCGH. For example, the recurrent CNVS reported in Table 1 and/or Table 28A can, at some stage, be easily screened for in the Rep cohort using PCR-based methods (e.g., junction fragment PCR assays).

To confirm the ancestry of each PML case, which was reported by the clinician, WGS data (Gencove, NY, USA) was generated on genomic DNA for all 185 cases. The Gencove platform uses low pass sequencing at a read depth of 0.1× that yields sufficient data (on the basis of SNPs) to ascertain ethnicity and “uniqueness” of a sample. This data enabled determination of:

-   -   A. Actual ethnicity, as opposed to relying on the         clinician-reported ethnicity;     -   B. Whether any of the 185 PML samples were duplicates. Because         PML is a rare disorder, it is possible that affected individuals         may have been seen multiple times by different medical centers.         None of the 185 samples were found to be duplicates. Gencove         reports the following categories of ancestries/ethnicities (full         name is following by abbreviation used in parentheses): Americas         (AMERICAS), Ashkenazi Jewish (ASHKENAZI), Bengal (BENGALI),         Central Africa (CAFRICA), Central Asia (CASIA), Eastern Africa         (EAFRICA), East Asia (EASIA), Eastern Mediterranean (EMED),         Finland (FINLAND), Central Indian subcontinent (INDPAK),         Northern Africa (NAFRICA), North-central Asia (NCASIA), Middle         East (NEAREAST), Northeast Asia (NEASIA), Northeast Europe         (NEEUROPE), Northern and Central Europe (NEUROPE), Northern         Italy (NITALY), Northern British Isles (NNEUROPE), Oceania         (OCEANIA), Southern Africa (SAFRICA), Scandinavia (SCANDINAVIA),         Southeast Asia (SEASIA), Southern Indian subcontinent (SSASIA),         Southwestern Europe (SWEUROPE), Anatolia, Caucasus, Iranian         Plateau (TURK-IRAN-CAUCASUS), and Western Africa (WAFRICA). To         simplify interpretation of the PML patient variants using public         databases, such as gnomAD and the 1000 genomes project (TGP),         Gencove ethnicities were combined to determine the highest         percentage ethnicity for either European ancestry (corresponding         to NFE in gnomAD and EUR in TGP) or African ancestry         (corresponding to AFR in gnomAD and in TGP). The following         Gencove ethnicities were combined:         NFE/EUR=(EMED+NEEUROPE+NEUROPE+NITALY+NNEUROPE+SCANDINAVIA+SWEUROPE)         and AFR=(CAFRICA+EAFRICA+NAFRICA+SAFRICA+WAFRICA). The majority         of PML patients could be readily assigned as NFE/EUR or AFR         ethnicity, but a few individuals were binned according to their         closest ethnicity (e.g., patients with predominantly ASHKENAZI         and TURK-IRAN-CAUCASUS ancestry were assigned as NFE/EUR).

TABLE 46 Complete list of 185 PML cases in the Discovery (n = 70) and Replication (n = 115) cohorts aCGH Primary Primary Cohort Sample ID Gender Expt ID Disease Ethnicity Dis MVGS1116-8a F 3006 MS NFE Dis MVGS1359 F 3117 MS NFE Dis MVGS1368 F 3118 MS NFE Dis MVGS540-374b M 3005 MS NFE Dis MVGS540-393b F 3004 MS NFE Dis MVGS694-6a F 3007 Other NFE Dis MVGS811-13a M 3009 HIV AFR Dis MVGS995-4a M 3010 MS NFE Dis PML1 F 3127 HIV NFE Dis PML10 F 3157 HIV NFE Dis PML12 F 3159 HIV NFE Dis PML13 M 3160 HIV NFE Dis PML14 M 3161 HIV NFE Dis PML15 M 3194 HIV AFR Dis PML16 F 3163 HIV AFR Dis PML17 M 3140 HIV NFE Dis PML18 M 3141 HIV NFE Dis PML19 M 3164 HIV AFR Dis PML2 M 3126 Blood Cancers NFE Dis PML20 M 3143 HIV AFR Dis PML21 M 3144 HIV NFE Dis PML22 M 3145 HIV NFE Dis PML23 F 3165 HIV NFE Dis PML25 F 3166 HIV NFE Dis PML26 M 3167 HIV NFE Dis PML27 M 3168 HIV NFE Dis PML28 F 3151 MS NFE Dis PML29 M 3152 HIV AFR Dis PML3 F 3155 MS NFE Dis PML30 M 3153 HIV NFE Dis PML31 F 3154 HIV AFR Dis PML32 M 3169 HIV NFE Dis PML33 M 3170 HIV NFE Dis PML35 F 3171 HIV NFE Dis PML36 F 3172 HIV NFE Dis PML37 M 3173 HIV AFR Dis PML38 M 3174 HIV NFE Dis PML39 M 3175 HIV AFR Dis PML4 M 3156 HIV NFE Dis PML40 F 3273 HIV AFR Dis PML41 M 3177 HIV NFE Dis PML43 M 3178 HIV NFE Dis PML44 M 3179 HIV NFE Dis PML45 F 3180 Blood Cancers NFE Dis PML46 M 3196 HIV NFE Dis PML48 M 3197 Other NFE Dis PML49 M 3183 HIV NFE Dis PML5 M 3125 HIV AFR Dis PML50 M 3198 HIV AFR Dis PML51 M 3185 HIV NFE Dis PML52 F 3186 Blood Cancers NFE Dis PML53 M 3187 Other NFE Dis PML54 F 3188 HIV NFE Dis PML55 F 3189 HIV NFE Dis PML56 M 3190 HIV NFE Dis PML57 F 3191 Blood Cancers NFE Dis PML58 M 3192 HIV AFR Dis PML59 M 3193 HIV AFR Dis PML6 M 3124 HIV NFE Dis PML60 M 3199 HIV NFE Dis PML61 F 3200 HIV AFR Dis PML62 F 3201 HIV AFR Dis PML63 M 3202 HIV AFR Dis PML64 M 3203 HIV AFR Dis PML65 M 3204 HIV AFR Dis PML66 M 3205 HIV AFR Dis PML68 F 3278 MS NFE Dis PML69 M 3279 Other NFE Dis PML72 F 3282 HIV AFR Dis PML9 M 3132 HIV NFE Rep PBPML100 F n/a Blood Cancers NFE Rep PBPML101 M n/a Blood Cancers NFE Rep PBPML102 F n/a Blood Cancers NFE Rep PBPML103 M n/a Other NFE Rep PBPML104 F n/a Blood Cancers NFE Rep PBPML105 M n/a Other NFE Rep PBPML106 M n/a Other NFE Rep PBPML107 M n/a Blood Cancers NFE Rep PBPML108 F n/a Blood Cancers NFE Rep PBPML109 M n/a Blood Cancers NFE Rep PBPML110 M n/a HIV AFR Rep PBPML111 M n/a HIV AFR Rep PBPML112 M n/a Blood Cancers NFE Rep PBPML113 M n/a HIV NFE Rep PBPML114 M n/a Blood Cancers NFE Rep PBPML115 F n/a Other NFE Rep PBPML116 F n/a HIV NFE Rep PBPML117 M n/a HIV NFE Rep PBPML118 M n/a HIV NFE Rep PBPML119 M n/a Other NFE Rep PBPML120 M n/a HIV NFE Rep PBPML121 M n/a HIV NFE Rep PBPML122 M n/a HIV NFE Rep PBPML123 F n/a MS NFE Rep PBPML124 M n/a Other NFE Rep PBPML125 M n/a MS NFE Rep PBPML126 M n/a Other NFE Rep PBPML127 F n/a Other NFE Rep PBPML128 M n/a HIV AFR Rep PBPML129 F n/a HIV AFR Rep PBPML130 M n/a Blood Cancers NFE Rep PBPML131 M n/a HIV NFE Rep PBPML132 F n/a HIV AFR Rep PBPML133 M n/a HIV NFE Rep PBPML134 F n/a HIV AFR Rep PBPML135 F n/a HIV NFE Rep PBPML136 F n/a Other NFE Rep PBPML137 M n/a HIV NFE Rep PBPML138 M n/a HIV NFE Rep PBPML139 F n/a MS NFE Rep PBPML140 M n/a HIV NFE Rep PBPML141 M n/a HIV AFR Rep PBPML142 M n/a HIV NFE Rep PBPML143 M n/a HIV NFE Rep PBPML144 F n/a HIV AFR Rep PBPML145 M n/a HIV NFE Rep PBPML146 M n/a Other NFE Rep PBPML147 M n/a HIV NFE Rep PBPML148 M n/a HIV AFR Rep PBPML149 M n/a Blood Cancers NFE Rep PBPML150 M n/a HIV NFE Rep PBPML151 M n/a HIV AFR Rep PBPML152 M n/a Other NFE Rep PBPML153 M n/a HIV NFE Rep PBPML154 F n/a MS NFE Rep PBPML155 M n/a HIV NFE Rep PBPML156 F n/a Blood Cancers NFE Rep PBPML157 M n/a HIV NFE Rep PBPML158 F n/a Other NFE Rep PBPML159 M n/a HIV NFE Rep PBPML160 F n/a Blood Cancers NFE Rep PBPML161 F n/a HIV AFR Rep PBPML162 M n/a HIV NFE Rep PBPML163 F n/a Blood Cancers NFE Rep PBPML164 M n/a HIV NFE Rep PBPML165 F n/a HIV AFR Rep PBPML166 M n/a HIV NFE Rep PBPML167 M n/a HIV NFE Rep PBPML168 F n/a MS NFE Rep PBPML169 M n/a HIV NFE Rep PBPML170 M n/a HIV AFR Rep PBPML171 M n/a HIV NFE Rep PBPML172 F n/a Blood Cancers NFE Rep PBPML173 M n/a Other NFE Rep PBPML174 M n/a Other NFE Rep PBPML175 F n/a HIV AFR Rep PBPML176 F n/a Blood Cancers NFE Rep PBPML177 M n/a HIV NFE Rep PBPML178 M n/a HIV NFE Rep PBPML179 M n/a HIV NFE Rep PBPML180 F n/a HIV AFR Rep PBPML181 M n/a HIV NFE Rep PBPML182 M n/a HIV NFE Rep PBPML183 M n/a HIV AFR Rep PBPML184 F n/a HIV AFR Rep PBPML185 M n/a HIV NFE Rep PBPML186 F n/a HIV AFR Rep PBPML187 M n/a HIV NFE Rep PBPML188 M n/a HIV AFR Rep PBPML189 F n/a HIV NFE Rep PBPML190 M n/a HIV AFR Rep PBPML191 F n/a HIV AFR Rep PBPML77 M n/a HIV NFE Rep PBPML78 M n/a HIV NFE Rep PBPML79 F n/a HIV NFE Rep PBPML80 F n/a HIV AFR Rep PBPML81 M n/a HIV NFE Rep PBPML82 F n/a HIV NFE Rep PBPML83 M n/a HIV AFR Rep PBPML84 M n/a HIV AFR Rep PBPML85 F n/a HIV AFR Rep PBPML86 M n/a Other AFR Rep PBPML87 F n/a HIV NFE Rep PBPML88 M n/a Other NFE Rep PBPML89 M n/a HIV AFR Rep PBPML90 M n/a HIV NFE Rep PBPML91 F n/a Blood Cancers NFE Rep PBPML92 F n/a HIV NFE Rep PBPML93 M n/a HIV AFR Rep PBPML94 M n/a Blood Cancers NFE Rep PBPML95 F n/a MS NFE Rep PBPML96 F n/a HIV NFE Rep PBPML97 M n/a Other NFE Rep PBPML98 M n/a Other NFE Rep PBPML99 F n/a Other NFE Table 46 represents the complete set of PML patients in the Discovery (Dis) or Replication (Rep) cohorts. The Dis cohort is equivalent to the patients listed in Table 7 except for PML67, for which insufficient DNA was available to generate WES data. Table 46 also lists the Sample ID, Gender, aCGH Expt ID (also reported in Table 11), Primary Disease, and Primary Ethnicity (based on Gencove ancestry analysis). Besides MS and HIV, the Primary Disease categories included Blood Cancers (mainly leukemias and lymphomas) and Other (miscellaneous conditions such as anemia, lymphopenia, sarcoidosis, and transplant patients).

Example 27—Updated Sequence Analysis Pipeline

High-throughput sequencing and sequence analysis methods are continually being developed to improve the quality of the data and results. A new approach, complimenting the previous approach, was used for the analysis of the Dis and Rep cohort WES data. Google's DeepVariant (DV) caller (github.com/google/deepvariant) was used for variant calling (see Poplin et al. (2018) Nat Biotechnol. November; 36(10):983-987). Using GRCh37 as the reference genome, BWA-aligned BAM files for each PML sample (Dis or Rep cohort) was run through the DV caller. Variant inclusion criteria were: DP≥10 (site depths were calculated again directly from the BAM files, with constraints for Base Quality>10 and Mapping Quality>20, and DP<10 were treated as “NA”), VAF>0.2 for heterozygous calls (VAF<0.2 were treated as “NA”), and VAF>0.8 for homozygous calls (VAF<0.8 were treated as heterozygous calls). Annotation of DV-called variants was performed using dbNSFP (see Liu et al. (2016) Hum Mutat. 2016 March; 37(3):235-41).

Variant burden analyses were performed using similar criteria as was used for variants reported in Tables 14, 15, 38, and 39, except that DV-called variants for the PML cases was used as input. The Dis and Rep cohorts were analyzed separately, with separate output files being generated for heterozygous (het) and homozygous (hom) variants. For simplicity, the genes listed in Tables 6, 25A, 25B, 26, and 31 were combined into a non-redundant list of 705 genes. The 705-gene list was compared to all genes that were found in the annotation reports for the two cohorts (Dis and Rep), which yielded a non-redundant gene list of 663 genes that were used for the DV pipeline variant burden analyses. In addition to the 663-gene analyses, a parallel set of all-genes (all ˜20,000 human genome genes) analyses were generated. To summarize, for each variant observed, a total count was made of the number of individuals in the PML cohorts that possessed the variant, and this was similarly done for comparison in three different unselected population cohorts: gnomAD exome (WES data), gnomAD genome (WGS data), and TGP exome (WES data). Fishers Exact Test (FET) and Odds Ratio (OR) were calculated to identify statistically significant variants with the highest OR values.

TABLE 47 663 genes analyzed for the 185 PML cases (DV pipeline) RefSeq IUIS- Cross- Gene Gene 334 Disease referenced Number Symbol Gene Model tables (GN) ACADM no unknown Table 6 157 ACD no AD AR Table 31 493 ACKR1 no AD AR Table 6 158 ACP5 yes AR Table 6 159 ACTB yes AD Table 31 494 ACTN4 no unknown Table 31 495 ADA yes AR Table 25B; Table 26 1 ADA2 yes AR Table 31 496 ADAM17 yes AR Table 31 497 ADAR yes AD AR Table 6 160 ADARB1 no unknown Table 6 2 ADGRL2 no unknown Table 31 498 ADK no unknown Table 6 161 AGBL4 no unknown Table 6 3 AICDA yes AD AR Table 6 162 AIRE yes AD AR Table 31 499 AK2 yes AR Table 6 163 ALG12 no AR Table 6 164 ALPL no unknown Table 6 165 ANP32B no unknown Table 31 500 AP1S3 yes AR Table 31 501 AP3B1 yes AR Table 6 166 AP3B2 no unknown Table 6 167 AP3D1 yes AR Table 6 168 APOBEC3A no unknown Table 6 4 APOBEC3B no unknown Table 6 6 APOL1 yes unknown Table 6 169 ARHGEF7 no unknown Table 6 8 ARPC1B yes AR Table 31 502 ASH1L no unknown Table 6 170 ASTN2 no unknown Table 6 9 ATG12 no unknown Table 31 503 ATG16L1 no unknown Table 31 504 ATG5 no unknown Table 31 505 ATG7 no unknown Table 31 506 ATG9A no unknown Table 31 507 ATL2 no unknown Table 6 171 ATM yes AR Table 6 172 ATP6AP1 yes XLR Table 31 508 ATR no unknown Table 6 173 AUH no unknown Table 6 10 B2M yes AR Table 31 509 BACH1 no unknown Table 6 11 BACH2 yes unknown Table 6 174 BAG3 no AR Table25A; Table 25B 175 BCL10 yes AR Table 6 176 BCL11B yes AD Table 31 510 BCL2 no unknown Table 31 511 BDKRB2 no unknown Table 6 12 BLK no AD Table 31 512 BLM yes AR Table 6 177 BLNK yes AR Table 6 178 BLOC1S6 no AR Table 6 179 BMPR2 no unknown Table 6 13 BRD4 no unknown Table 31 513 BTK yes XLR Table25A; Table 25B 180 BTLA no unknown Table 31 514 C11orf65 no unknown Table 6 181 C1QA yes AR Table 6 182 C1QB yes AR Table 6 183 C1QC yes AR Table 6 184 C1R yes AR Table 31 515 C1S yes AR Table 31 516 C2 yes AR Table 31 517 C3 yes AD AR Table 31 518 C4A yes AR Table 31 519 C4B yes AR Table 31 520 C5 yes AR Table 31 521 C5AR1 no unknown Table 6 185 C6 yes AR Table 31 522 C7 yes AR Table 31 523 C8A yes AR Table 31 524 C8B yes AR Table 31 525 C8G yes AR Table 31 526 C9 yes AR Table 31 527 CAD no AR Table 31 528 CAMLG no unknown Table 31 529 CAPZB no unknown Table 6 186 CARD11 yes AD AR Table 6 187 CARD14 yes AD Table 31 530 CARD9 yes AR Table 6 188 CASP10 yes AD Table 31 531 CASP8 yes AR Table 6 189 CAV1 no unknown Table 31 532 CCBE1 yes AR Table 31 533 CCDC22 no XLR Table 31 534 CCL11 no unknown Table 6 190 CCL2 no unknown Table 6 191 CCL5 no unknown Table 6 192 CCR2 no unknown Table 6 193 CCR5 no unknown Table 6 194 CCZ1 no unknown Table 31 535 CD180 no unknown Table 6 195 CD19 yes AR Table 6 196 CD209 no unknown Table 6 197 CD22 no unknown Table 31 536 CD247 yes AR Table 6 198 CD27 yes AR Table 6 199 CD274 no unknown Table 31 537 CD276 no unknown Table 31 538 CD300LF no unknown Table 6 23 CD34 no unknown Table 6 201 CD36 no AR Table 31 539 CD37 no unknown Table 31 540 CD38 no unknown Table 31 541 CD3D yes AR Table 6 202 CD3E yes AR Table 6 203 CD3G yes AR Table 6 204 CD40 yes AR Table 6 205 CD40LG yes XLR Table25A; Table 25B 206 CD46 yes AD Table 31 542 CD5 no unknown Table 31 543 CD55 yes unknown Table 6 207 CD59 yes AR Table 6 208 CD70 yes AR Table 31 544 CD72 no unknown Table 31 545 CD74 no unknown Table 31 546 CD79A yes AR Table 6 209 CD79B yes AR Table 6 210 CD81 yes AR Table 6 211 CD84 no unknown Table 31 547 CD8A yes AR Table 6 212 CD93 no unknown Table 31 548 CDCA7 yes AR Table 6 213 CDKN1B no unknown Table 6 24 CEBPB no unknown Table 6 214 CEBPE yes AR Table 31 549 CENPM no unknown Table 6 25 CFB yes AD AR Table 31 550 CFD yes AR Table 31 551 CFH yes AD AR Table 31 552 CFHR1 yes AD AR Table 31 553 CFHR2 yes AD AR Table 31 554 CHAR3 yes AD AR Table 31 555 CHAR4 yes AD AR Table 31 556 CHAR5 yes AD AR Table 31 557 CFI yes AD AR Table 31 558 CFP yes XLR Table 31 559 CFTR yes AR Table 31 560 CHD2 no unknown Table 31 561 CHD7 yes AD Table 6 215 CHEK1 no unknown Table 6 216 CIITA yes AR Table 6 217 CLCN7 yes AD Table 6 218 CLEC16A no unknown Table 31 562 CLPB yes AR Table 31 563 COG4 no unknown Table 6 26 COG6 no AR Table 6 219 COMMD6 no unknown Table 6 27 COPA yes AD Table 31 564 CORO1A yes AR Table 6 220 CR2 yes AR Table 6 221 CRADD no unknown Table 6 28 CRTC3 no unknown Table 6 222 CSF2RA yes XLR Table 31 565 CSF2RB yes AR Table 31 566 CSF3R yes AR Table 6 223 CTC1 yes AR Table 31 567 CTLA4 yes AD Table 6 224 CTPS1 yes AR Table 6 225 CTSC yes AR Table 6 226 CX3CR1 no unknown Table 6 227 CXCL1 no unknown Table 31 568 CXCL10 no unknown Table 31 569 CXCL12 no unknown Table 6 228 CXCL5 no unknown Table 31 570 CXCL8 no unknown Table 31 571 CXCL9 no unknown Table 6 229 CXCR1 no unknown Table 6 230 CXCR3 no unknown Table 31 572 CXCR4 yes AD Table 6 231 CXorf40A no unknown Table 6 232 CYBA yes AR Table 31 573 CYBB yes XLR Table 6 233 CYP2S1 no unknown Table 6 234 DCLRE1B yes AR Table 31 574 DCLRE1C yes AR Table 6 235 DDX1 no unknown Table 6 236 DDX58 yes AD Table 6 237 DHX58 no unknown Table 6 238 DKC1 yes XLR Table 6 239 DNAJC21 yes AR Table 31 575 DNASE1L3 yes AR Table 31 576 DNASE2 yes AR Table 31 577 DNER no unknown Table 6 31 DNMT3B yes AR Table 25B 240 DOCK2 yes AR Table 6 241 DOCK8 yes AR Table25A; Table 25B 242 DSC1 no unknown Table 6 243 DUSP16 no unknown Table 6 32 EBF1 no unknown Table 31 578 EDIL3 no unknown Table 6 34 EEA1 no unknown Table 6 35 EGF no unknown Table 31 579 EGR1 no unknown Table 6 244 EHF no unknown Table 6 36 ELANE yes AD Table 6 245 EMB no unknown Table 6 37 EPG5 yes AR Table 6 246 ERCC6L2 yes AR Table 31 580 ETF1 no unknown Table 6 247 ETV6 no AD Table 6 38 EXTL3 yes AR Table 31 581 F9 no unknown Table 6 248 FAAP24 yes AR Table 31 582 FADD yes AR Table 31 583 FAS yes AD Table 6 249 FASLG yes AD Table 6 250 FAT4 yes AR Table 31 584 FCER2 no unknown Table 31 585 FCGR2A no AD AR Table 6 251 FCGR3A yes AR Table 6 252 FCN3 yes AR Table 6 253 FERMT3 yes AR Table 31 586 FEZ1 no unknown Table 6 254 FHL2 no unknown Table 6 39 FIS1 no unknown Table 31 587 FOS no unknown Table 6 255 FOXH1 no unknown Table 6 256 FOXN1 yes AR Table 6 257 FOXP3 yes XLR Table 6 258 FPR1 yes unknown Table 6 259 FPR2 no unknown Table 6 41 FPR3 no unknown Table 6 42 FUK no unknown Table 6 43 G6PC3 yes AR Table 6 260 G6PD yes XLD Table 31 588 GATA2 yes AD Table 6 261 GDA no unknown Table 6 44 GDPD4 no unknown Table 6 45 GFI1 yes AD Table 6 262 GINS1 yes AR Table 31 589 GOLGB1 no unknown Table 6 263 GPATCH2 no unknown Table 6 46 GPC5 no unknown Table 6 47 GPRC5A no unknown Table 6 264 GRAP2 no unknown Table 6 265 GRIA3 no unknown Table 6 51 GTPBP4 no unknown Table 6 52 HAX1 yes AR Table 6 266 HCN1 no unknown Table 6 53 HELLS yes AR Table 6 267 HERC5 no unknown Table 31 590 HERC6 no unknown Table 31 591 HEXA no unknown Table 6 54 HIVEP1 no unknown Table 6 268 HIVEP2 no AD Table 6 269 HIVEP3 no unknown Table 6 270 HK2 no unknown Table 6 55 HMGB1 no unknown Table 31 592 HMOX1 yes AR Table 31 593 HNRNPLL no unknown Table 6 271 HP no unknown Table 6 272 HPCAL1 no unknown Table 6 273 HPR no unknown Table 6 57 HTR2A no unknown Table 6 274 HYOU1 yes AR Table 31 594 ICAM1 no unknown Table 31 595 ICOS yes AR Table 6 275 ICOSLG no unknown Table 31 596 IDI1 no unknown Table 6 276 IDI2 no unknown Table 6 59 IDO2 no unknown Table 6 61 IFI35 no unknown Table 31 597 IFIH1 yes AD Table 6 277 IFIT1 no unknown Table 31 598 IFIT2 no unknown Table 31 599 IFIT3 no unknown Table 31 600 IFNAR1 no unknown Table 6 278 IFNAR2 yes AR Table 6 279 IFNG no unknown Table 6 280 IFNGR1 yes AD AR Table 6 281 IFNGR2 yes AD AR Table 6 282 IFNLR1 no unknown Table 6 62 IGHM yes AR Table 31 601 IGHMBP2 no unknown Table 31 602 IGKC yes AR Table 31 603 IGLL1 yes AR Table 6 283 IKBKB yes AD AR Table 6 284 IKBKG yes XLD XLR Table 6 285 IKZF1 yes AD Table 6 286 IL10 yes AR Table 6 287 IL10RA yes AR Table 6 288 IL10RB yes AR Table 6 289 IL12B yes AR Table 6 290 IL12RB1 yes AR Table 6 291 IL17F yes AD Table 6 292 IL17RA yes AR Table 6 293 IL17RC yes AR Table 31 604 IL1B no unknown Table 6 294 IL1RN yes AR Table 31 605 IL21 yes AR Table 6 295 IL21R yes AD AR Table 6 296 IL2RA yes AR Table 6 297 IL2RG yes XLR Table 6 298 IL3 no unknown Table 31 606 IL36RN yes AR Table 31 607 IL4 no unknown Table 31 608 IL4R no unknown Table 6 299 IL7 no unknown Table 6 300 IL7R yes AR Table 6 301 INO80 yes AR Table 31 609 INPP5D no unknown Table 31 610 IRAK1 yes XLR Table 31 611 IRAK4 yes AD AR Table 6 302 IRF2BP2 yes AD Table 31 612 IRF3 yes AD Table 6 303 IRF7 yes AR Table 6 304 IRF8 yes AD AR Table 6 305 IRGM no unknown Table 6 306 ISG15 yes AR Table 6 307 ITCH yes AR Table 31 613 ITGAM no unknown Table 31 614 ITGB2 yes AR Table 31 615 ITK yes AR Table 25B 308 ITPKB no unknown Table 31 616 ITSN1 no unknown Table 31 617 ITSN2 no unknown Table 6 309 JAGN1 yes AR Table 6 310 JAK1 yes AD AR Table 31 618 JAK3 yes AR Table 6 311 JMY no unknown Table 6 312 JUN no unknown Table 6 313 KANK1 no unknown Table 6 65 KAT6B no unknown Table 6 66 KCTD7 no unknown Table 6 67 KDM6A yes XLD XLR Table 31 619 KITLG no unknown Table 6 314 KMT2D yes AD Table 31 620 KRAS no AD Table 31 621 LAMTOR2 yes AR Table 6 315 LARP4B no unknown Table 6 69 LAT yes AR Table 31 622 LCK yes AR Table 25B 316 LCP2 no unknown Table 6 317 LIG1 yes AR Table 6 318 LIG4 yes AR Table 6 319 LPIN2 yes AR Table 31 623 LRBA yes AR Table 6 322 LRRK2 no unknown Table 31 624 LYST yes AR Table 6 323 MAGEA9B no unknown Table 6 325 MAGT1 yes XLR Table 6; Table 25A 326 MALL no unknown Table 6 72 MALT1 yes AR Table 6 327 MAP3K14 yes AR Table 31 625 MAP3K2 no unknown Table 6 328 MAPK1 no unknown Table 6 329 MAPK3 no unknown Table 6 330 MAPK9 no unknown Table 6 73 MASP2 yes AR Table 31 626 MAVS no unknown Table 6 331 MB21D1 no unknown Table 31 627 MBL2 no AD Table 31 628 MCEE no unknown Table 6 74 MCM4 yes AR Table 31 629 MCM5 no AR Table 31 630 MDC1 no unknown Table 31 631 MECP2 no XLD XLR Table 6 332 MEF2C no AD Table 31 632 MEFV yes AD AR Table 31 633 MEX3C no unknown Table 6 333 MFN1 no unknown Table 31 634 MFN2 no unknown Table 31 635 MGAT5 no unknown Table 6 75 MKL1 yes AR Table 6 89 MLH1 no AD AR Table 31 636 MMP9 no unknown Table 31 637 MOGS yes AR Table 31 638 MON1A no unknown Table 31 639 MON1B no unknown Table 31 640 MRE11A no AR Table 6 334 MS4A1 yes AR Table 6 335 MSH2 no AD AR Table 31 641 MSH5 no AR Table 31 642 MSH6 yes AR Table 31 643 MSN yes unknown Table 6 336 MTHFD1 yes AR Table 6 337 MVK yes AD AR Table 31 644 MX1 no unknown Table 31 645 MX2 no unknown Table 31 646 MYD88 yes AD AR Table 6 338 MYSM1 yes AR Table 31 647 NBAS yes AR Table 31 648 NBN yes AD AR Table 6 339 NCF1 yes AR Table 31 649 NCF2 yes AR Table 31 650 NCF4 yes AR Table 31 651 NCSTN yes AD Table 31 652 NFAT5 yes AD Table 31 653 NFIC no unknown Table 6 340 NFIL3 no unknown Table 6 92 NFKB1 yes AD Table 6 341 NFKB2 yes AD Table 6 342 NFKBIA yes AD Table 6 343 NHEJ1 yes AR Table 6 344 NHP2 yes AR Table 31 654 NLRC4 yes AD Table 31 655 NLRP1 yes AR Table 31 656 NLRP12 yes AD Table 6 93 NLRP2 no unknown Table 31 657 NLRP3 yes AD Table 6 345 NLRX1 no unknown Table 31 658 NOD1 no unknown Table 31 659 NOD2 yes AD Table 6 346 NOP10 yes AR Table 31 660 NQO2 no unknown Table 6 94 NRIP1 no unknown Table 6 95 NSMCE3 yes AR Table 31 661 OAS1 no AD Table 31 662 OAS2 no unknown Table 31 663 OAS3 no unknown Table 31 664 OASL no unknown Table 31 665 ORAI1 yes AD AR Table 6 347 ORC4 no AR Table 31 666 OSTM1 yes AR Table 6 348 OTULIN yes AR Table 31 667 OVOL2 no unknown Table 6 98 PARN yes AD AR Table 31 668 PCCA no AR Table 31 669 PCCB no AR Table 31 670 PDCD1 no unknown Table 31 671 PDCD1LG2 no unknown Table 31 672 PDE3B no unknown Table 6 99 PDGFRA no unknown Table 6 100 PDSS2 no unknown Table 6 101 PEPD yes AR Table 31 673 PGM3 yes AR Table 6 349 PHACTR4 no unknown Table 6 102 PIAS1 no unknown Table 6 103 PIAS2 no unknown Table 6 350 PIK3CD yes AD Table 6 104 PIK3R1 yes AD AR Table 6 351 PINK1 no unknown Table 31 674 PKHD1 no unknown Table 6 105 PLAU no unknown Table 31 675 PLAUR no unknown Table 31 676 PLCG1 no unknown Table 31 677 PLCG2 yes AD Table 6 352 PLD1 no AR Table 31 678 PLEKHM1 yes AR Table 31 679 PLK1 no unknown Table 31 680 PLXNB1 no unknown Table 31 681 PMM2 no AR Table 31 682 PMS2 yes AR Table 6 353 PNP yes unknown Table 25B 354 PNPLA4 no unknown Table 6 107 PNPT1 no unknown Table 6 108 POLA1 yes XLR Table 6 355 POLE yes AR Table 6 356 POLE2 yes AR Table 31 683 PPM1A no unknown Table 31 684 PPP2R3B no unknown Table 6 109 PRF1 yes AD AR Table 6 357 PRKCB no unknown Table 6 110 PRKCD yes AR Table 6 358 PRKCH no unknown Table 6 111 PRKDC yes AD AR Table 6 359 PRKN no unknown Table 31 685 PROC no unknown Table 6 360 PRRC2A no unknown Table 31 686 PSEN1 yes AD Table 31 687 PSENEN yes AD Table 31 688 PSMA7 no unknown Table 31 689 PSMB8 yes AR Table 6 361 PSTPIP1 yes AD Table 6 112 PTEN yes AD Table 6 362 PTPN2 no unknown Table 6 113 PTPRC yes AR Table 6 363 PTPRN2 no unknown Table 6 114 PURA no unknown Table 6 364 RAB27A yes AR Table 6 365 RAB37 no unknown Table 6 115 RAB5A no unknown Table 31 690 RAB5B no unknown Table 31 691 RAB5C no unknown Table 31 692 RAB7A no unknown Table 6 366 RABGEF1 no unknown Table 6 367 RAC2 yes AD Table 6 368 RAD50 no unknown Table 31 693 RAD51 no unknown Table 6 369 RAG1 yes AD AR Table25A; Table 25B 370 RAG2 yes AR Table 6 371 RANBP2 yes AD Table 31 694 RASGRP1 yes AR Table 31 695 RBCK1 yes AR Table 6 372 RBFOX1 no unknown Table 6 116 RCC1 no unknown Table 6 117 RELA no unknown Table 31 696 RELB yes AR Table 31 697 RFX5 yes AR Table 6 373 RFXANK yes AR Table 6 374 RFXAP yes AR Table 6 375 RGCC no unknown Table 6 118 RHOH yes AR Table 31 698 RHOQ no unknown Table 6 119 RIPK1 no unknown Table 6 376 RIPK3 no unknown Table 6 377 RLTPR yes AR Table 31 699 RNASE3 no unknown Table 6 120 RNASEH2A yes AR Table 6 379 RNASEH2B yes AR Table 6 380 RNASEH2C yes AR Table 6 381 RNASEL no unknown Table 6 382 RNF125 no unknown Table 31 700 RNF168 yes AR Table 6 383 RNF31 yes AR Table 6 384 RORC yes AR Table 31 701 RPSA yes AD Table 31 702 RPTOR no unknown Table 6 123 RSAD2 no unknown Table 31 703 RTEL1 yes AR Table 6 386 SALL2 no unknown Table 6 388 SAMD9 yes AD Table 31 704 SAMD9L yes AD Table 31 705 SAMHD1 yes AR Table 6 389 SBDS yes AR Table 6 390 SEMA3E yes AD Table 31 706 SERPINA1 no AR Table 31 707 SERPINB2 no unknown Table 31 708 SERPINB4 no unknown Table 6 124 SERPINB6 no unknown Table 6 125 SERPING1 yes AD Table 31 709 SH2D1A yes XLR Table 6 391 SH3BP2 yes AD Table 31 710 SHARP1N no unknown Table 6 392 SKIV2L no AR Table 6 393 SLC17A5 no unknown Table 6 127 SLC29A3 yes AR Table 31 711 SLC35C1 yes AR Table 31 712 SLC37A4 yes AR Table 6 394 SLC3A2 no unknown Table 6 126 SLC46A1 yes AR Table 6 395 SLC7A7 no AR Table 31 713 SLC8A1 no unknown Table 6 396 SLC9A1 no unknown Table 31 714 SMAD2 no unknown Table 6 397 SMAD3 no unknown Table 6 398 SMAD4 no unknown Table 6 399 SMARCAL1 yes AR Table 31 715 SMARCD2 yes AR Table 31 716 SMC3 no AD Table 31 717 SMURF2 no unknown Table 31 718 SNAP29 no unknown Table 6 400 SNCA no unknown Table 6 429 SNHG3 no unknown Table 6 128 SNX10 yes AR Table 6 430 SNX5 no unknown Table 6 130 SOCS2 no unknown Table 6 131 SP110 yes AR Table 6 431 SP140 no unknown Table 6 432 SPINK5 yes AR Table 6 433 SQSTM1 no unknown Table 6 434 SRP54 yes AD Table 31 719 ST8SIA5 no unknown Table 6 133 STAT1 yes AD AR Table25A; Table 25B 436 STAT2 yes AR Table 6 437 STAT3 yes AD Table 25B 438 STAT5B yes AR Table 6 439 STIM1 yes AD AR Table 6 440 STIM2 no unknown Table 6 134 STK3 no unknown Table 25B; Table 26 135 STK4 yes AR Table 6 441 STN1 yes AR Table 31 720 STX11 yes AR Table 6 442 STXBP2 yes AD AR Table 6 443 SYNCRIP no unknown Table 6 444 TAN yes AR Table 6 446 TAP2 yes AR Table 6 447 TAPBP yes unknown Table 6 448 TAZ yes XLR Table 6 449 TBC1D15 no unknown Table 31 721 TBC1D16 no unknown Table 6 136 TBC1D17 no unknown Table 31 722 TBK1 yes AD Table 6 450 TBX1 yes AD Table 6 451 TBXT no unknown Table 6 445 TCF3 yes AD Table 31 723 TCIRG1 yes AD AR Table 6 452 TCN2 yes AR Table 31 724 TEK no AD Table 31 725 TERT yes AD AR Table 31 727 TFPI no unknown Table 31 728 TFRC yes AR Table 31 729 THBD yes AD Table 31 730 THBS1 no unknown Table 31 731 TICAM1 yes AD AR Table 6 453 TINF2 yes AD Table 31 732 TIRAP yes AR Table 31 733 TLR3 yes AD Table 6 454 TLR4 no unknown Table 6 455 TMC6 yes AR Table 31 734 TMC8 yes AR Table 31 735 TMEM173 yes AD Table 6 456 TNF no unknown Table 6 457 TNFAIP3 yes AD Table 6 458 TNFRSF10A no unknown Table 6 138 TNFRSF11A yes AD AR Table 6 459 TNFRSF11B no AR Table 6 460 TNFRSF13B yes AD AR Table 6 461 TNFRSF13C yes AR Table 6 139 TNFRSF17 no unknown Table 31 736 TNFRSF18 no unknown Table 6 140 TNFRSF1A yes AD Table 31 737 TNFRSF4 yes AR Table 6 462 TNFRSF8 no unknown Table 6 463 TNFSF10 no unknown Table 31 738 TNFSF11 yes AR Table 6 464 TNFSF12-TNFSF13 yes AD Table 6 465 TNFSF13B no unknown Table 31 740 TNIP1 no unknown Table 31 741 TP53 no AD AR Table 6 466 TP53AIP1 no unknown Table 31 742 TPP1 yes AD AR Table 31 743 TPP2 yes AR Table 31 744 TRAC yes AR Table 31 745 TRAF3 yes AD Table 6 467 TRAF3IP2 yes AR Table 31 746 TRAF6 no unknown Table 6 468 TRAFD1 no unknown Table 6 141 TREX1 yes AD AR Table 6 469 TRIM25 no unknown Table 31 747 TRIM37 no AR Table 31 748 TRNT1 yes AR Table 6 470 TRPM2 no unknown Table 6 142 TTC37 yes AR Table 31 749 TTC7A yes AR Table 6 471 TYK2 yes AR Table 25B 144 UBD no unknown Table 31 750 UBE2N no unknown Table 6 145 UNC119 no AD Table 6 472 UNC13D yes AR Table 6 473 UNC93B1 yes unknown Table 6 474 UNG yes AR Table 6 475 USB1 yes AR Table 31 751 USP15 no unknown Table 31 752 USP18 yes AR Table 6 476 USP20 no unknown Table 6 477 USP21 no unknown Table 31 753 USP25 no unknown Table 31 754 USP3 no unknown Table 31 755 VAPA no unknown Table 6 478 VAV1 no unknown Table 31 756 VCP no AD Table 6 479 VDAC1 no unknown Table 6 480 VDR no AD AR Table 31 757 VEGFA no unknown Table 31 758 VPS13B yes AR Table 6 481 VPS45 yes AR Table 6 482 VSTM1 no unknown Table 6 147 VWA2 no unknown Table 6 148 WAS yes XLR Table25A; Table 25B 483 WASHC5 no AD AR Table 31 759 WDR1 yes AR Table 31 760 WEE1 no unknown Table 6 484 WIPF1 yes AR Table 6; Table 25B 485 WRAP53 yes AR Table 31 761 XAF1 no unknown Table 31 762 XIAP yes XLD XLR Table 6 486 YBX1 no unknown Table 6 487 YWHAZ no unknown Table 6 488 ZAP70 yes AD AR Table 6 489 ZBTB24 yes AR Table 6 490 For the 663-genes list in Table 47, the following are provided: RefSeq Gene Symbol, whether the gene is included in the NIS-334 list (Picard et al. (2018) J Clin Immunol. 38(1):96-128; Bousfiha et al. (2018) J Clin Immunol. 38(1):129-143), the Disease Model, Cross-referenced tables that also list a subset of the 663 genes, and Gene Number.

In some embodiments, stricter criteria can be used for the Disease Model designation. For example, Table 6 uses AR, AD, XLR, and XLD disease models based on the OMIM entries irrespective of whether the genetic disease is a classical immunodeficiency disorder. Whereas, Table 47 lists AR, AD, XLR, and XLD entries only for those genes that are on the NIS-334 gene list. For example, the gene PKHD1 causes AR polycystic kidney disease and is listed as an AR disease in Table 6 but with an “unknown” Disease Model in Table 47. However, those skilled in the art understand that additional disease phenotypes are often added to the clinical picture once more patients are identified. In Burgmaier et al. 2019 (Sci Rep. 9(1):7919), patients are reported to have the immune phenotypes of thrombocytopenia, anemia, and leukopenia.

Example 28—DV Pipeline Variant Burden Summary Data

Top variants from the variant burden analyses were identified on the basis of filtering criteria that were applied to both the Dis and Rep PML cohorts (including a subset of functional annotation), followed by determining the subset of filtered variants that were found in both cohorts. The filtering criteria used were:

-   -   A. 663-genes (het and hom files), IMPACT=HIGH or MODERATE, ≥2         EUR cases or ≥1 AFR case, FET≤0.1, OR>1     -   B. All-genes (het and hom files) used 3 sets of filters:         -   1. IMPACT=HIGH, ≥3 EUR cases or ≥1 AFR case, FET≤0.05, OR>1         -   2. IMPACT=MODERATE, VARIANT CLASS=deletion or insertion, ≤3             EUR cases or ≥1 AFR case, FET≤0.05, OR>1         -   3. IMPACT=MODERATE, VARIANT CLASS=SNV, PolyPhen=damaging and             SIFT=D (deleterious), 3 EUR cases or 2 AFR case, FET 0.05,             OR>1             After finding the set of overlapping variants for the Dis             and Rep cohorts according to the above filters, they were             further assessed for biology of the genes using PubMed and             ranked as follows: 1=strong biology, 2=medium biology,             3=unknown biology. Variants were also excluded for: 1) very             high PML case counts (more likely to be false positives), 2)             high frequency in one ethnicity but not the other (greater             likelihood that the variant is benign as compared to a             variant that is rare in both the EUR and AFR ethnicities),             and 3) presence in a chr X gene (such variants are             challenging to interpret as gender needs to be taken into             account). The top 27 variants from this set of analyses and             filtering criteria are listed in Tables 50A and 50B.

TABLE 50A Top 27 variants from DV pipeline variant burden analyses IUI Poly SEQ Gene Variant (hg19) Source S-334 Consequence Impact Phen SIFT ID AIRE 21-45708278-G-A 663 het yes missense moderate prob. tol. 3268, AFR dam. 3523 ATM 11-108106443-T-A 663 hom yes missense moderate beign tol. 3517 AFR C8B 1-57409459-C-A 663 het yes missense moderate prob. tol. 3015, AFR dam. 3502 CFHR2 1-196918605-A-G 663 het yes missense moderate beign tol. 3505 AFR DNASE1L3 3-58191230-G-T 663 het yes missense moderate beign tol. 3508 AFR DNER 2-230579019-G-A 663 het no missense moderate beign del. 3507 NFE FCN2 9-137779251-G-A all het no missense moderate prob. del. 3515 NFE dam. FCN3 1-27699670-AG-A 663 het yes frameshift high n/a; n/a; 3500 NFE LOF LOF GFI1 1-92946625-G-C 663 het yes missense moderate beign tol. 3503 AFR HIVEP3 1-42047208-C-G 663 het no missense moderate beign tol. 3501 AFR IFIH1 2-163136505-C-G US yes Splice high n/a; n/a; 1041, 10240205; donor LOF LOF 3506 663 het NFE; all het NFE IGLL1 22-23915583-T-C 663 het yes missense moderate beign tol. 3524 NFE IGLL1 22-23915745-G-A US yes missense moderate beign del. 1325, 10240205 3525 LIG1 19-48643270-C-T 663 het yes missense moderate prob. del. 3522 AFR dam. LRBA 4-151793903-T-C 663 het yes missense moderate beign tol. 3509 NFE LY9 1-160769595-AG-A all het no frameshift high n/a; n/a; 3504 AFR LOF LOF MCM5 22-35806756-G-A 663 het no missense moderate prob. tol. 3273, NFE dam. 3526 MDC1 6-30673359-T-G 663 het no missense moderate beign tol. 3511 NFE NQO2 6-3015818-G-A 663 het no missense moderate prob. del. 3510 AFR dam. PKHD1 6-51798908-C-T 663 het no missense moderate prob. del. 3514 AFR dam. PLCG2 16-81942175-A-G US yes missense moderate beign del. 1263, 10240205 3519 PRAM1 19-8564523-T-G all het no missense moderate prob. del. 3521 NFE; all dam. het AFR SERPINA1 14-94847262-T-A 663 het yes missense moderate prob. del. 3214, NFE dam. 3518 STXBP2 19-7712287-G-C US yes missense moderate prob. del. 1291, 10240205; dam. 3520 663 ht NFE TAP1 6-32814942-C-T 663 het yes missense moderate prob. del. 3512 NFE; dam. 663 hom AFR TAP1 6-32816772-C-A 663 het yes missense moderate beign tol. 3213 NFE; 663 hom AFR TCIRG1 11-67818269-G-A US yes missense mod beign tol. 1185, 10240205 3516 Table 50A lists the Gene, Variant position (hg19), Source of the variant (663-genes or all-genes het or horn variant burden files, and/or from U.S. Pat. No. 10,240,205), functional prediction (Consequence, Impact, PolyPhen, SIFT), and SEQ IDs. Loss of Function variants (LOF) are indicated in the Polyphen and SIFT columns as n/a/LOF (e.g., no amino acid prediction information was available from these algorithms but the gnomAD annotation indicates “LOF: High-confidence”).

TABLE 50B Top 27 variants from DV pipeline variant burden analyses, distribution of PML cases by cohort (Dis and Rep) and ethnicity (EUR and AFR) Dis EUR Rep EUR Dis AFR Rep AFR (n = 49) (n = 87) (n = 21) (n = 28) Gene Variant (hg19) Het Hom Het Hom Het Hom Het Hom AIRE 21-45708278-G-A 0 0 0 0 1 0 1 0 ATM 11-108106443-T-A 2 0 0 0 7 3 8 3 C8B 1-57409459-C-A 3 0 0 0 1 0 1 0 CFBR2 1-196918605-A-G 0 0 0 0 1 0 2 0 DNASE1L3 3-58191230-G-T 0 0 0 0 1 0 1 0 DNER 2-230579019-G-A 4 0 4 0 0 0 0 0 FCN2 9-137779251-G-A 3 0 3 0 0 0 1 0 FCN3 1-27699670-AG-A 5 0 7 0 0 0 2 0 GFI1 1-92946625-G-C 2 0 0 0 1 0 1 0 HIVEP3 1-42047208-C-G 8 0 8 0 2 0 3 0 IFIE11 2-163136505-C-G 6 0 5 0 1 0 0 0 IGLL1 22-23915583-T-C 2 0 3 0 0 0 0 0 IGLL1 22-23915745-G-A 2 0 1 0 1 0 0 0 LIG1 19-48643270-C-T 1 0 0 0 1 0 1 0 LRBA 4-151793903-T-C 6 0 9 0 0 0 1 0 LY9 1-160769595-AG-A 0 0 0 0 1 0 1 0 MCM5 22-35806756-G-A 3 0 4 0 0 0 0 0 MDC1 6-30673359-T-G 2 0 5 0 0 0 0 0 NQO2 6-3015818-G-A 0 0 0 0 1 0 2 0 PKHD1 6-51798908-C-T 0 0 0 0 2 0 1 0 PLCG2 16-81942175-A-G 3 0 3 0 4 0 1 0 PRAM1 19-8564523-T-G 27 1 14 4 6 0 4 1 SERPINA1 14-94847262-T-A 7 0 12 0 0 0 1 0 STXBP2 19-7712287-G-C 2 0 2 0 0 0 0 0 TAP1 6-32814942-C-T 6 0 9 1 6 2 5 2 TAP1 6-32816772-C-A 6 0 9 1 6 2 5 2 TCIRG1 11-67818269-G-A 0 0 0 0 4 0 3 0 Table 50B shows the same top 27 variants listed in Table 50A, but with the distribution of number of PML cases that had a het or hom genotype and a breakdown by cohort (Dis or Rep) and ethnicity (EUR or AFR).

Example 29—DV Pipeline Variant Burden Statistical Analyses

The set of 27 variants from the DV pipeline variant burden analyses (see Tables 50A and 50B) were ranked based on FET and OR values for four types of analyses: EUR only, AFR only, EUR+AFR normalized (norm.) wherein the gnomAD cohort sizes were adjusted to match the relative proportion of EUR (NFE in gnomAD) and AFR PML cases in the total cohort (n=185), and EUR+AFR summed (sum.) wherein the subject data for the gnomAD NFE and AFR cohorts were simply added together. Three sets of statistical analyses were performed using three publically available resources (gnomAD exome, gnomAD genome, and TGP exome), but only the gnomAD exome analyses are presented in Tables 51-62 as the results were comparable for nearly all variants. For each set of 3 tables (tier 1, tier 2, and tiers 1 and 2 combined), FET and OR were calculated for all 27 variants, variants were sorted on OR (descending), and variants with FET>0.05 were excluded. For Tier 1 variants (Tables 51, 54, 57, and 60), preference was given to variants with OR>3 and only moderate frequency in PML cases (e.g., PRAM1 19-8564523-T-G was considered too frequent). The “Reads” listed in the tables corresponds to the read counts in the sequencing data (e.g., the number of individuals sampled for the variant). Tables 51 and 54 also have a Panel rank wherein the top 7 EUR variants and top 10 AFR variants are assigned a rank that is used in Tables 63A-64B.

TABLE 51 7 EUR variants (tier 1) with FET and OR values PML All EUR gnomAD NFE Dominant Model Panel Gene Variant (hg19) Het Hom Reads Het Hom Reads FET OR rank IGLL1 22-23915745-G-A 3 0 136 42 0 56703 1.77E-04 30.42 1 MDC1 6-30673359-T-G 7 0 136 302 0 54608 1.34E-05 9.76 2 STXBP 19-7712287-G-C 4 0 136 267 0 55798 4.46E-03 6.30 3 FCN2 9-137779251-G-A 6 0 136 461 1 56457 9.85E-04 5.59 4 IGLL1 22-23915583-T-C 5 0 136 446 0 56811 4.70E-03 4.82 5 MCM5 22-35806756-G-A 7 0 136 665 7 56875 1.28E-03 4.54 6 IFIH1 2-163136505-C-G 11 0 136 1225 6 56438 2.19E-04 3.95 7

TABLE 52 9 EUR variants (tier 2) with FET and OR values PML All EUR gnomAD NFE Dominant Model Gene Variant (hg19) Het Hom Reads Het Hom Reads FET OR PRAM1 19-8564523-T-G 41 5 136 2076 250 30728 1.65E-18 6.24 ATM 11-108106443-T-A 2 0 136 143 0 56802 4.74E-02 5.91 TAN 6-32816772-C-A 15 1 135 2250 26 55054 1.61E-04 3.12 TAN 6-32814942-C-T 15 1 136 2258 28 55157 1.80E-04 3.08 PLCG2 16-81942175-A-G 6 0 136 831 2 56290 1.64E-02 3.07 FCN3 1-27699670-AG-A 12 0 136 1826 24 56778 1.77E-03 2.87 DNER 2-230579019-G-A 8 0 136 55 3 2670 1.32E-02 2.81 SERPINA1 14-94847262-T-A 19 0 136 3946 105 56878 4.25E-03 2.12 LRBA 4-151793903-1-C 15 0 136 3046 62 55340 1.32E-02 2.08

TABLE 53 16 EUR variants (tiers 1 and 2) with FET and OR values PML All EUR gnomAD NFE Dominant Model Gene Variant (hg19) Het Hom Reads Het Hom Reads FET OR IGLL1 22-23915745-G-A 3 0 136 42 0 56703 1.77E−04 30.42  MDC1 6-30673359-T-G 7 0 136 302 0 54608 1.34E−05 9.76 STXBP2 19-7712287-G-C 4 0 136 267 0 55798 4.46E−03 6.30 PRAM1 19-8564523-T-G 41 5 136 2076 250 30728 1.65E−18 6.24 ATM 11-108106443-T-A 2 0 136 143 0 56802 4.74E−02 5.91 FCN2 9-137779251-G-A 6 0 136 461 1 56457 9.85E−04 5.59 IGLL1 22-23915583-T-C 5 0 136 446 0 56811 4.70E−03 4.82 MCM5 22-35806756-G-A 7 0 136 665 7 56875 1.28E−03 4.54 IFIH1 2-163136505-C-G 11 0 136 1225 6 56438 2.19E−04 3.95 TAP1 6-32816772-C-A 15 1 135 2250 26 55054 1.61E−04 3.12 TAP1 6-32814942-C-T 15 1 136 2258 28 55157 1.80E−04 3.08 PLCG2 16-81942175-A-G 6 0 136 831 2 56290 1.64E−02 3.07 FCN3 1-27699670-AG-A 12 0 136 1826 24 56778 1.77E−03 2.87 DNER 2-230579019-G-A 8 0 136 55 3  2670 1.32E−02 2.81 SERPINA1 14-94847262-T-A 19 0 136 3946 105 56878 4.25E−03 2.12 LRBA 4-151793903-T-C 15 0 136 3046 62 55340 1.32E−02 2.08

TABLE 54 10 AFR variants (tier 1) with FET and OR values PML All AFR gnomAD AFR Dominant Model Panel Gene Variant (hg19) Het Hom Reads Het Hom Reads FET OR rank LY9 1-160769595-AG-A 2 0 49  0 0 8123 3.52E−05 855.11  1 LIG1 19-48643270-C-T 2 0 49  1 0 8126 1.05E−04 339.72  2 PKHD1 6-51798908-C-T 3 0 49 15 0 8127 1.55E−04 35.15 3 AIRE 21-45708278-G-A 2 0 49 17 0 8079 5.70E−03 20.14 4 GFI1 1-92946625-G-C 2 0 49 19 0 7756 7.51E−03 17.29 5 CFHR2 1-196918605-A-G 3 0 49 37 0 8027 1.77E−03 14.07 6 NQO2 6-3015818-G-A 3 0 49 39 0 8128 1.97E−03 13.51 7 C8B 1-57409459-C-A 2 0 49 28 0 8128 1.38E−02 12.29 8 DNASE1L3 3-58191230-G-T 2 0 49 32 0 8126 1.75E−02 10.75 9 PLCG2 16-81942175-A-G 5 0 49 128  0 7719 1.42E−03  6.73 10 

TABLE 55 3 AFR variants (tier 2) with FET and OR values PML All AFR gnomAD AFR Dominant Model Gene Variant (hg19) Het Hom Reads Het Hom Reads FET OR PRAM1 19-8564523-T-G 10  1 49 136 4 6351 1.18E−08 12.82  HIVEP3 1-42047208-C-G 5 0 49 175 2 8041 4.67E−03 5.05 TCIRG1 11-67818269-G-A 7 0 49 318 1 8113 3.08E−03 4.07

TABLE 56 13 AFR variants (tiers 1 and 2) with FET and OR values PML All AFR gnomAD AFR Dominant Model Gene Variant (hg19) Het Hom Reads Het Hom Reads FET OR LY9 1-160769595-AG-A 2 0 49 0 0 8123 3.52E−05 855.11 LIG1 19-48643270-C-T 2 0 49 1 0 8126 1.05E−04 339.72 PKHD1 6-51798908-C-T 3 0 49 15 0 8127 1.55E−04 35.15 AIRE 21-45708278-G-A 2 0 49 17 0 8079 5.70E−03 20.14 GFI1 1-92946625-G-C 2 0 49 19 0 7756 7.51E−03 17.29 CFHR2 1-196918605-A-G 3 0 49 37 0 8027 1.77E−03 14.07 NQO2 6-3015818-G-A 3 0 49 39 0 8128 1.97E−03 13.51 PRAM1 19-8564523-T-G 10  1 49 136 4 6351 1.18E−08 12.82 C8B 1-57409459-C-A 2 0 49 28 0 8128 1.38E−02 12.29 DNASE1L3 3-58191230-G-T 2 0 49 32 0 8126 1.75E−02 10.75 PLCG2 16-81942175-A-G 5 0 49 128 0 7719 1.42E−03 6.73 HIVEP3 1-42047208-C-G 5 0 49 175 2 8041 4.67E−03 5.05 TCIRG1 11-67818269-G-A 7 0 49 318 1 8113 3.08E−03 4.07

TABLE 57 13 EU + AFR variants (tier 1) with FET and OR values (normalized) PML All gnomAD NFE + EUR + AFR AFR (norm.) Dominant Model Gene Variant (hg19) Het Hom Reads Het Hom Reads FET OR PKHD1 6-51798908-C-T 3 0 185 6 0 43916 5.99E−06 120.00 LY9 1-160769595-AG-A 2 0 185 6 0 43924 4.82E−04 79.75 CFHR2 1-196918605-A-G 3 0 185 10 0 43752 2.04E−05 72.02 NQO2 6-3015818-G-A 3 0 185 12 0 43941 3.18E−05 60.30 AIRE 21-45708278-G-A 2 0 185 8 0 43685 7.78E−04 59.62 IGLL1 22-23915745-G-A 4 0 185 58 0 43836 1.39E−04 16.67 TCIRG1 11-67818269-G-A 7 0 185 227 0 43910 6.39E−05 7.57 PML All gnomAD NFE + Gene Variant (hg19) EUR + AFR AFR (norm.) Dominant Model ATM 11-108106443-T-A 17  6 185 797 88  43909 6.97E−12 6.90 MDC1 6-30673359-T-G 7 0 185 251 0 42164 1.50E−04 6.57 PRAM1 19-8564523-T-G 51  6 185 1562 185  24271 2.94E−21 5.74 FCN2 9-137779251-G-A 7 0 185 342 1 43653 7.60E−04 4.96 STXBP2 19-7712287-G-C 4 0 185 198 0 43049 1.13E−02 4.78 PLCG2 16-81942175-A-G 11  0 185 645 1 43425 1.27E−04 4.19

TABLE 58 8 EUR + AFR variants (tier 2) with FET and OR values (normalized) PML All gnomAD NFE + EUR + AFR AFR (norm.) Dominant Model Gene Variant (hg19) Het Hom Reads Het Hom Reads FET OR TAP1 6-32816772-C-A 26 5 184 2144 52 42515 7.80E−09 3.72 TAP1 6-32814942-C-T 26 5 185 2140 53 42544 8.50E−09 3.70 GFI1 1-92946625-G-C 4 0 185 256 1 40597 3.16E−02 3.47 IGLL1 22-23915583-T-C 5 0 185 352 0 43910 1.78E−02 3.44 MCM5 22-35806756-G-A 7 0 185 494 5 43964 5.71E−03 3.43 IFIH1 2-163136505-C-G 12 0 185 910 4 43635 6.16E−04 3.24 FCN3 1-27699670-AG-A 14 0 185 1448 18 43889 5.84E−03 2.37 SERPINA1 14-94847262-T-A 20 0 185 2934 77 43966 4.05E−02 1.65

TABLE 59 21 EUR + AFR variants (tiers 1 and 2) with FET and OR values (normalized) PML All gnomAD NFE + EUR + AFR AFR (norm.) Dominant Model Gene Variant (hg19) Het Hom Reads Het Hom Reads FET OR PKHD1 6-51798908-C-T 3 0 185 6 0 43916 5.99E−06 120.00 LY9 1-160769595-AG-A 2 0 185 6 0 43924 4.82E−04 79.75 CFHR2 1-196918605-A-G 3 0 185 10 0 43752 2.04E−05 72.02 NQO2 6-3015818-G-A 3 0 185 12 0 43941 3.18E−05 60.30 AIRE 21-45708278-G-A 2 0 185 8 0 43685 7.78E−04 59.62 IGLL1 22-23915745-G-A 4 0 185 58 0 43836 1.39E−04 16.67 TCIRG1 11-67818269-G-A 7 0 185 227 0 43910 6.39E−05 7.57 ATM 11-108106443-T-A 17 6 185 797 88 43909 6.97E−12 6.90 MDC1 6-30673359-T-G 7 0 185 251 0 42164 1.50E−04 6.57 PRAM1 19-8564523-T-G 51 6 185 1562 185 24271 2.94E−21 5.74 FCN2 9-137779251-G-A 7 0 185 342 1 43653 7.60E−04 4.96 STXBP2 19-7712287-G-C 4 0 185 198 0 43049 1.13E−02 4.78 PLCG2 16-81942175-A-G 11 0 185 645 1 43425 1.27E−04 4.19 TAP1 6-32816772-C-A 26 5 184 2144 52 42515 7.80E−09 3.72 TAP1 6-32814942-C-T 26 5 185 2140 53 42544 8.50E−09 3.70 GFI1 1-92946625-G-C 4 0 185 256 1 40597 3.16E−02 3.47 IGLL1 22-23915583-T-C 5 0 185 352 0 43910 1.78E−02 3.44 MCM5 22-35806756-G-A 7 0 185 494 5 43964 5.71E−03 3.43 IFIH1 2-163136505-C-G 12 0 185 910 4 43635 6.16E−04 3.24 FCN3 1-27699670-AG-A 14 0 185 1448 18 43889 5.84E−03 2.37 SERPINA1 14-94847262-T-A 20 0 185 2934 77 43966 4.05E−02 1.65

TABLE 60 12 EUR + AFR variants (tier 1) with FET and OR values (summed) PML All gnomAD NFE + EUR + AFR AFR (sum.) Dominant Model Gene Variant (hg19) Het Hom Reads Het Hom Reads FET OR LY9 1-160769595-AG-A 2 0 185 8 0 64946 3.56E−04 88.57 PKHD1 6-51798908-C-T 3 0 185 18 0 64937 2.89E−05 59.42 AIRE 21-45708278-G-A 2 0 185 22 0 64592 2.15E−03 32.06 CFHR2 1-196918605-A-G 3 0 185 37 0 64650 2.09E−04 28.78 NQO2 6-3015818-G-A 3 0 185 41 0 64972 2.74E−04 26.11 IGLL1 22-23915745-G-A 4 0 185 146 0 64826 9.30E−04 9.79 PRAM1 19-8564523-T-G 51 6 185 2212 254 37079 5.81E−23 6.25 MDC1 6-30673359-T-G 7 0 185 411 0 62235 2.71E−04 5.91 FCN2 9-137779251-G-A 7 0 185 471 1 64574 4.92E−04 5.34 STXBP2 19-7712287-G-C 4 0 185 274 0 63462 9.08E−03 5.10 TCIRG1 11-67818269-G-A 7 0 185 512 1 64920 7.71E−04 4.94 PLCG2 16-81942175-A-G 11 0 185 959 2 64009 1.34E−04 4.15

TABLE 61 11 EUR + AFR variants (tier 2) with FET and OR values (summed) PML All gnomAD NFE + EUR + AFR AFR (sum.) Dominant Model Gene Variant (hg19) Het Hom Reads Het Hom Reads FET OR LIG1 19-48643270-C-T 3 0 185 281 0 64971 4.77E−02 3.79 MCM5 22-35806756-G-A 7 0 185 683 7 65003 3.97E−03 3.67 GFI1 1-92946625-G-C 4 0 185 361 1 60185 2.67E−02 3.65 IFIH1 2-163136505-C-G 12 0 185 1262 6 64538 3.48E−04 3.46 IGLL1 22-23915583-T-C 5 0 185 537 0 64915 1.98E−02 3.33 ATM 11-108106443-T-A 17 6 185 2755 333 64928 2.83E−05 2.84 TAP1 6-32814942-C-T 26 5 185 4070 149 62693 2.63E−06 2.79 TAP1 6-32816772-C-A 26 5 184 4101 149 62767 2.65E−06 2.79 FCN3 1-27699670-AG-A 14 0 185 2224 26 64892 6.97E−03 2.28 LRBA 4-151793903-T-C 16 0 185 3116 62 63322 4.01E−02 1.79 SERPINA1 14-94847262-T-A 20 0 185 4073 106 65006 2.30E−02 1.76

TABLE 62 23 EUR + AFR variants (tiers 1 and 2) with FET and OR values (summed) PML All gnomAD NFE + EUR + AFR AFR (sum.) Dominant Model Gene Variant (hg19) Het Hom Reads Het Hom Reads FET OR LY9 1-160769595-AG-A 2 0 185 8 0 64946 3.56E−04 88.57 PKHD1 6-51798908-CT-T 3 0 185 18 0 64937 2.89E−05 59.42 AIRE 21-45708278-G-A 2 0 185 22 0 64592 2.15E−03 32.06 CFHR2 1-196918605-A-G 3 0 185 37 0 64650 2.09E−04 28.78 NQO2 6-3015818-G-A 3 0 185 41 0 64972 2.74E−04 26.11 IGLL1 22-23915745-G-A 4 0 185 146 0 64826 9.30E−04 9.79 PRAM1 19-8564523-T-G 51 6 185 2212 254 37079 5.81E−23 6.25 MDC1 6-30673359-T-G 7 0 185 411 0 62235 2.71E−04 5.91 FCN2 9-137779251-G-A 7 0 185 471 1 64574 4.92E−04 5.34 STXBP2 19-7712287-G-C 4 0 185 274 0 63462 9.08E−03 5.10 TCIRG1 11-67818269-G-A 7 0 185 512 1 64920 7.71E−04 4.94 PLCG2 16-81942175-A-G 11 0 185 959 2 64009 1.34E−04 4.15 LIG1 19-48643270-C-T 3 0 185 281 0 64971 4.77E−02 3.79 MCM5 22-35806756-G-A 7 0 185 683 7 65003 3.97E−03 3.67 GFI1 1-92946625-G-C 4 0 185 361 1 60185 2.67E−02 3.65 IFIH1 2-163136505-C-G 12 0 185 1262 6 64538 3.48E−04 3.46 IGLL1 22-23915583-T-C 5 0 185 537 0 64915 1.98E−02 3.33 ATM 11-108106443-T-A 17 6 185 2755 333 64928 2.83E−05 2.84 TAP1 6-32814942-C-T 26 5 185 4070 149 62693 2.63E−06 2.79 TAP1 6-32816772-C-A 26 5 184 4101 149 62767 2.65E−06 2.79 FCN3 1-27699670-AG-A 14 0 185 2224 26 64892 6.97E−03 2.28 LRBA 4-151793903-T-C 16 0 185 3116 62 63322 4.01E−02 1.79 SERPINA1 14-94847262-T-A 20 0 185 4073 106 65006 2.30E−02 1.76

Example 30—Variant Panels with Diagnostic Yield and Population Impact Assessment

Variant panels consisting of the top 7 EUR variants (Table 51) and top 10 AFR variants (Table 54) were assessed for their non-redundant diagnostic yield in the PML cases (e.g., a PML case with 2 panel variants was counted only once). These panels were similarly assessed in TGP exome data from 440 AFR and 436 EUR subjects, whose GRCh37-referenced BAM files were downloaded and re-analyzed using the DV pipeline. Tables 63A and 64A show the results for EUR and AFR PML cases vs. TGP controls, respectively, wherein the PML Panel Frequency corresponds to the diagnostic yield and the Frequency Ratio reflects the level of enrichment of the panel variants in the PML cases. The FET and OR values correspond to the number of PML cases and TGP controls that have any one or more of 3 variants, 4 variants, etc. for a given panel.

Tables 63B and 64B contain the population impact assessment results as described in Tonk et al. (2016) Pharmacogenomics J. 17(4):386-392, for the following: Sensitivity, Specificity, Positive predictive value (PPV), Negative predictive value (NPV), Population attributable frequency (PAF), Number needed to treat (NNT), and Number needed to genotype (NNG).

TABLE 63A EUR 7-variant panel, diagnostic yield and FET and OR values EUR EUR PML PML TGP TGP Frequency Variants Cases Panel Subjects Panel Ratio Tested (n = 136) Frequency (n = 436) Frequency (PML/TGP) FET OR EUR Top 3 14 0.103 5 0.011 8.98 4.02E−06 9.89 EUR Top 4 19 0.140 7 0.016 8.70 6.90E−08 9.95 EUR Top 5 24 0.176 11 0.025 6.99 7.45E−09 8.28 EUR Top 6 31 0.228 16 0.037 6.21 1.32E−10 7.75 EUR Top 7 40 0.294 30 0.069 4.27 1.06E−10 5.64

TABLE 63B EUR 7-variant panel, population impact assessment Relative Risk Variants Risk Difference Tested Sensitivity Specificity PPV NPV (RR) (RD) PAF NNT NNG EUR Top 3  9.1% 99.0% 10.7%  98.8% 8.94 0.09 0.08 11 953 EUR Top 4 15.1% 98.2% 10.2%  98.9% 9.04 0.09 0.13 11 574 EUR Top 5 17.6% 97.5% 8.4% 98.9% 7.66 0.07 0.15 14 503 EUR Top 6 22.7% 96.4% 7.6% 99.0% 7.24 0.07 0.20 15 394 EUR Top 7 25.8% 94.2% 5.5% 99.0% 5.38 0.04 0.21 22 366

TABLE 64A AFR 10-variant panel, diagnostic yield and FET and OR values AFR AFR PML PML TGP TGP Frequency Variants Cases Panel Subjects Panel Ratio Tested (n = 49) Frequency (n = 440) Frequency (PML/TGP) FET OR AFR Top 6 14 0.286 5 0.011 25.14 1.29E−11 34.80 AFR Top 7 17 0.347 6 0.014 25.44 3.97E−14 38.43 AFR Top 8 19 0.388 6 0.014 28.44 3.18E−16 45.81 AFR Top 9 20 0.408 6 0.014 29.93 2.66E−17 49.89 AFR Top 10 23 0.469 10  0.023 20.65 1.90E−18 38.04

TABLE 64B AFR 10-variant panel, population impact assessment Relative Risk Variants Risk Difference Tested Sensitivity Specificity PPV NPV (RR) (RD) PAF NNT NNG AFR Top 6 22.6% 99.2% 26.4% 99.0% 25.89 0.25 0.22 4 355 AFR Top 7 31.7% 98.8% 25.9% 99.1% 28.73 0.25 0.31 4 251 AFR Top 8 40.0% 98.6% 26.9% 99.2% 33.78 0.26 0.39 4 198 AFR Top 9 47.0% 98.3% 26.2% 99.3% 37.09 0.25 0.46 4 168 AFR Top 10 56.5% 96.7% 18.4% 99.4% 31.22 0.18 0.55 6 141

Example 31—Variant Panels with Summary Information

Table 65 shows the breakdown of PML cases with a variant from the set of 17 variants (7 EUR and 10 AFR, Tables 51 and 54). In general, they are distributed across genders, ethnicities, and primary diseases. For example, all 7 EUR variants are found in two or more Primary Diseases (MS, HIV, Blood Cancers, Other). In contrast, about half of the 10 AFR variants are found only in HIV PML patients, but this is not surprising given the large proporation of AFR HIV PML cases (48 of 49) in the PML cohort (see Table 46).

Table 66 lists the dbSNP ID numbers for the set of 17 variants (7 EUR and 10 AFR, Tables 51 and 54), along with PubMed PMID numbers for supporting biology in the literature (see also Tables 6 and 31 for additional PMID citations for a subset of the genes).

TABLE 65 EUR 7-variant and AFR 10-variant panels, distribution of PML cases by cohort, gender, ethnicity, and primary disease Dis Rep PML Blood Panel Cohort Cohort TOTAL Males Females AFR EUR MS HIV cancers Other Gene Variant Source (n = (n = (n = (n = (n = (n = (n = (n = (n = (n = (n = (hg19) Rank 70) 115) 185) 118) 67) 49) 136) 15) 125) 22) 23) IGLL1 22-23915745- EUR 1 3 1 4 2 2 1 3 1 3 0 0 G-A MDC1 6-30673359- EUR 2 2 7 9 9 0 1 8 0 8 0 1 T-G STXBP2 19-7712287- EUR 3 2 2 4 1 3 0 4 2 1 0 1 G-C FCN2 9-137779251- EUR 4 3 4 7 4 3 1 6 2 4 1 0 G-A IGLL1 22-23915583- EUR 5 2 3 5 1 4 0 5 0 1 4 0 T-C MCM5 22-35806756- EUR 6 3 4 7 4 3 0 7 1 5 0 1 G-A IFIH1 2-163136505- EUR 7 7 5 12  9 3 1 11  1 8 1 2 C-G LY9 1-160769595- AFR 1 1 1 2 1 1 2 0 0 1 0 1 AG-A LIG1 19-48643270- AFR 2 2 1 3 3 0 2 1 0 3 0 0 C-T PKHD1 6-51798908- AFR 3 2 1 3 1 2 3 0 0 3 0 0 C-T AIRE 21-45708278- AFR 4 1 1 2 0 2 2 0 0 2 0 0 G-A GFI1 1-92946625- AFR 5 3 1 4 2 2 2 2 0 3 1 0 G-C CFHR2 1-196918605- AFR 6 1 2 3 2 1 3 0 0 3 0 0 A-G NQO2 6-3015818- AFR 7 1 2 3 2 1 3 0 0 3 0 0 G-A C8B 1-57409459- AFR 8 4 1 5 2 3 2 3 1 3 1 0 C-A DNASE 3-58191230- AFR 9 1 1 2 2 0 2 0 0 2 0 0 1L3 G-T PLCG2 16-81942175- AFR 10 7 4 11  9 2 5 6 1 8 0 2 A-G

TABLE 66 EUR 7-variant and AFR 10-variant panels, dbSNP IDs and supporting biology Panel Source Supporting Biology-PubMed Gene Variant (hg19) dbSNP ID Rank (PMID) IGLL1 22-23915745-G-A rs143780139 EUR 1 31291582 MDC1 6-30673359-T-G rs143258964 EUR 2 30453211, 30541848 STXBP2 19-7712287-G-C rs35490401 EUR 3 28983403, 29599780 FCN2 9-137779251-G-A rs76267164 EUR 4 20375618, 25251245, 28894916, 30747617, 30868077 IGLL1 22-23915583-1-C rs1064421 EUR 5 31291582 MCM5 22-35806756-G-A rs2230933 EUR 6 27414250 IFIH1 2-163136505-C-G rs35337543 EUR 7 22648297, 28716935, 28475461, 28553952, 30201512 LY9 1-160769595-AG-A rs763811636 AFR 1 15905546,26667173, 27054584, 27482100, 30791129 LIG1 19-48643270-C-T rs3730947 AFR 2 30395541 PKHD1 6-51798908-C-T rs199589074 AFR 3 31138820 AWE 21-45708278-G-A rs148012328 AFR 4 31167928 GFI1 1-92946625-G-C rs149914857 AFR 5 26447191, 31004086 CFHR2 1-196918605-A-G rs148175483 AFR 6 29686068 NQO2 6-3015818-G-A rs148024596 AFR 7 27692612 C8B 1-57409459-C-A rs139498867 AFR 8 31270218 DNASE1L3 3-58191230-G-T rs12491947 AFR 9 28533778, 30593563, 30026744 PLCG2 16-81942175-A-G rs75472618 AFR 10 28714976

Example 32—Updated Drug Information

Immunosuppessive medications are a broad and expanding class of therapeutics, which includes generic versions of biologics (termed biosimilars). Drugs, such as those on the market that may be linked to PML risk, either now or in the future, include but are not limited to: diroximel fumarate (e.g. VUMERITY), siponimod (e.g. MAYZENT), golimumab (e.g. SIMPONI), elotuzumab (e.g. EMPLICITI), idebenone, ravulizimab-cwvz (e.g. (ULTOMIRIS), letrozole (e.g. FEMARA), voriconazole (e.g. VFEND), dalfampridine (e.g. AMPYRA), ambrisentan (e.g. LETAIRIS), pegfilgrastim (e.g. NEULASTA), simvastatin, adrenocorticotropic hormone, lipoic acid, and oxcarbazepine.

Immunosuppressive medications undergoing clinical trials that may linked to PML risk before or after drug approval include but are not limited to: elezanumab, nerispirdine, daprolizumab pegol, etrolizumab, abrilumab, evobrutinib, amiselimod, ceralifimod, clemastine, sunphenon epigallocatechin-gallate, and andrographolides (a botanical medicinal herb also known as IB-MS).

In addition, other molecules of interest include but are not limited to BNZ-1, IMU-838, SAR442168/PRN2246, BIIB033, BIIB059, BIIB061, AJM300, EK-12 (a neuropeptide combination of metenkefalin and tridecactide), and CHS-131.

Some drugs of interest as immunosuppressive medications have alternate names reported in FDA databases, such as fingolimod vs. fingolimod hydrochloride, mycophenolate mofetil vs. mycophenolate mofetil hydrochloride, tacrolimus vs. tacrolimus anhydrous, bendamustine vs. bendamustine hydrochloride, doxorubicin vs. doxorubicin hydrochloride, and certolizumab vs. certolizumab pegol.

Some HIV treatments have also been linked to cases of PML in the FDA database, such as ritonavir (e.g. NORVIR), enfuvirtida (e.g. FUZEON), and maraviroc (e.g. SELZENTRY).

Approved medications and/or molecules of interest that have the same mechanism of action as natalizumab, and therefore may linked to PML, include but are not limited to levocabastine, TR-14035, and R-411.

TABLE 67 Examples of biosimilars Orignal Biosimilar Brand Generic Biosimilar Brand/ Name Name Name Code Name Rituxan rituximab rituximab-abbs Truxima Rituxan rituximab rituximab-pvvr Ruxience Rituxan rituximab Rimimyo Rituxan rituximab Rixathon Rituxan rituximab ABP 798 Rituxan rituximab RTXM83 Remicade infliximab infliximab-dyyb Inflectra Remicade infliximab infliximab-abda Renflexis Remicade infliximab infliximab-qbtx Ixifi/Zessly Remicade infliximab ABP 710 Remicade infliximab Remsima Humira adalimumab adalimumab-atto Amjevita Humira adalimumab adalimumab-adaz Hyrimoz Humira adalimumab adalimumab-bwwd Hadalmia Humira adalimumab adalimumab-adbm Cyltezo Humira adalimumab Hullo Humira adalimumab Imraldi Humira adalimumab PF-06410293 Humira adalimumab CT-P17 Humira adalimumab CHS-1420 Humira adalimumab M923/BAX923 Humira adalimumab MYL-1401A Humira adalimumab LBAL Humira adalimumab MSB11022 (Idacio/Kromeya) Humira adalimumab GP2017 Humira adalimumab BCD-057 Humira adalimumab ONS-3010 Humira adalimumab AVT02 Enbrel etanercept etanercept-szzs Erelzi Enbrel etanercept etanercept-ykro Eticovo Enbrel etanercept CT-P05 Enbrel etanercept Benepali Enbrel etanercept Altebrel Avastin bevacizumab bevacizumab-awwb Mvasi Avastin bevacizumab bevacizumab-bvzr Zirabev Avastin bevacizumab AB8 Avastin bevacizumab CT-P16 Solaris eculizumab SB12 Solaris eculizumab ABP 959 Neulasta pegfilgrastim pegfilgrastim-jmdb Fulphila Neulasta pegfilgrastim pegfilgrastim-cbqv Udenyca Neulasta pegfilgrastim Pelmeg Neulasta pegfilgrastim PF-06881894

While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby

EMBODIMENTS

1. A method of treating a condition in a subject in need thereof, comprising: administering a therapeutically effective amount of one or more immunosuppressive medications to the subject, wherein the subject is identified as not having a high risk of developing progressive multifocal leukoencephalopathy (PML) by a genetic test. 2. A method of treating a condition in a subject in need of immunosuppressive medication therapy, comprising: administering a therapeutically effective amount of one or more immunosuppressive medications to the subject, wherein the subject has a decreased risk of progressive multifocal leukoencephalopathy (PML) due to an infection of the brain by John Cunningham virus (JCV), wherein the subject's decreased risk is due to the absence of one or more genetic variations that occur at a frequency of 10% or less in a population of human subjects with PML. 3. A method of treating a condition in a subject in need of immunosuppressive medication therapy, comprising: administering a therapeutically effective amount of one or more immunosuppressive medications to the subject, wherein the subject has a decreased risk of progressive multifocal leukoencephalopathy (PML) due to an infection of the brain by John Cunningham virus (JCV), wherein the subject's decreased risk is due to the absence of one or more genetic variations that occur at a frequency of more than 10% in a population of human subjects with PML 4. The method of paragraph 1 or 2, wherein the risk is due to the absence of one or more genetic variations that occur at a frequency of 10% or less in a population of human subjects with PML and with an immune deficiency. 5. The method of paragraph 1 or 2, wherein the subject's decreased risk is due to the absence of one or more genetic variations that occur at a frequency of 10% or less in a population of human subjects with PML and without an immune deficiency. 6. The method of paragraph 3, wherein the risk is due to the absence of one or more genetic variations that occur at a frequency of more than 10% in a population of human subjects with PML and with an immune deficiency. 7. The method of paragraph 3, wherein the subject's decreased risk is due to the absence of one or more genetic variations that occur at a frequency of more than 10% in a population of human subjects with PML and without an immune deficiency. 8. A method of treating a condition in a subject in need of immunosuppressive medication therapy, comprising: administering a therapeutically effective amount of one or more immunosuppressive medications to the subject, wherein the subject has a decreased risk of progressive multifocal leukoencephalopathy (PML) due to an infection of the brain by John Cunningham virus (JCV), and wherein the subject's decreased risk is due to the absence of one or more genetic variations that occur at a frequency of 1% or less in a population of human subjects without PML. 9. The method of paragraph 1 or 8, wherein the risk is due to the absence of one or more genetic variations that occur at a frequency of 1% or less in a population of human subjects without PML and with an immune deficiency. 10. The method of paragraph 1 or 8, wherein the risk is due to the absence of one or more genetic variations that occur at a frequency of 1% or less in a population of human subjects without PML and without an immune deficiency. 11. A method of treating a condition in a subject in need of immunosuppressive medication therapy, comprising: administering a therapeutically effective amount of one or more immunosuppressive medications to the subject, wherein the subject has a decreased risk of progressive multifocal leukoencephalopathy (PML) due to an infection of the brain by John Cunningham virus (JCV), and wherein the risk is due to the absence of one or more genetic variations that occur at a frequency of 10% or less in a population of human subjects with an immune deficiency. 12. The method of paragraph 1 or 11, wherein the risk is due to the absence of one or more genetic variations that occur at a frequency of 10% or less in a population of human subjects with an immune deficiency and with PML. 13. The method of paragraph 1 or 11, wherein the risk is due to the absence of one or more genetic variations that occur at a frequency of 10% or less in a population of human subjects with an immune deficiency and without PML. 14. A method of treating a condition in a subject in need of immunosuppressive medication therapy, comprising: administering a therapeutically effective amount of one or more immunosuppressive medications to the subject, wherein the subject has a decreased risk of progressive multifocal leukoencephalopathy (PML) due to an infection of the brain by John Cunningham virus (JCV), and wherein the subject's decreased risk is due to the absence of one or more genetic variations that occur at a frequency of 0.1% or less in a population of human subjects without an immune deficiency. 15. The method of paragraph 1 or 14, wherein the risk is due to the absence of one or more genetic variations that occur at a frequency of 1% or less in a population of human subjects without an immune deficiency and with PML. 16. The method of paragraph 14, wherein the risk is due to the absence of one or more genetic variations that occur at a frequency of 1% or less in a population of human subjects without an immune deficiency and without PML. 17. A method of treating a condition in a subject in need of immunosuppressive medication therapy, comprising: administering a therapeutically effective amount of one or more immunosuppressive medications to the subject, wherein the subject has a decreased risk of progressive multifocal leukoencephalopathy (PML) due to an infection of the brain by John Cunningham virus (JCV), wherein the subject's decreased risk is due to the absence of one or more genetic variations in the subject, wherein the one or more genetic variations have an odds ratio (OR) of 3 or more, and wherein the OR is: [D_(D)/D_(N)]/[N_(D)/N_(N)], wherein: D_(D) is the number of subjects in a diseased cohort of subjects with the one or more genetic variations; D_(N) the number of subjects in the diseased cohort without the one or more genetic variations; N_(D) is the number of subjects in a non-diseased cohort of subjects with the one or more genetic variations; and N_(N) is the number of subjects in the non-diseased cohort without the one or more genetic variations. 18. The method of paragraph 17, wherein the diseased cohort or non-diseased cohort comprises at least 100 human subjects. 19. The method of paragraph 18, wherein the at least 100 human subjects comprises

-   -   (a) at least 10 human subjects with PML,     -   (b) at least 10 human subjects with an immune deficiency,     -   (c) at least 10 human subjects without an immune deficiency,     -   (d) at least 10 human subjects without PML, or     -   (e) any combination thereof.         20. The method of any one of paragraphs 2-19, wherein the         subject's decreased risk is due to the absence of one or more         genetic variations that has an odds ratio (OR) of at least 3, 4,         5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45 or 50.         21. A method of treating a condition in a subject in need of         immunosuppressive medication therapy, comprising: administering         a therapeutically effective amount of one or more         immunosuppressive medications to a subject with a condition,         wherein the subject has a decreased risk of progressive         multifocal leukoencephalopathy (PML) due to an infection of the         brain by John Cunningham virus (JCV), wherein the subject's         decreased risk is due to the presence of gene sequences that do         not comprise any of 2 or more genetic variations in a panel         comprising the 2 or more genetic variations.         22. The method of paragraph 21, wherein the 2 or more genetic         variations comprise at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,         13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 75, 100 genetic         variations.         23. The method of paragraph 21 or 22, wherein the gene sequences         are wild-type gene sequences.         24. The method of any one of paragraphs 1 to 23, wherein the         condition is a cancer, an organ transplant, or an autoimmune         disease.         25. The method of paragraph 24, wherein the condition is an         autoimmune disease.         26. The method of paragraph 25, wherein the autoimmune disease         is selected from the group consisting of Addison disease,         Anti-NMDA receptor encephalitis, antisynthetase syndrome,         Aplastic anemia, autoimmune anemias, Autoimmune hemolytic         anemia, Autoimmune pancreatitis, Behcet's Disease, bullous skin         disorders, Celiac disease—sprue (gluten-sensitive enteropathy),         chronic fatigue syndrome, Chronic inflammatory demyelinating         polyneuropathy, chronic lymphocytic leukemia, Crohn's disease,         Dermatomyositis, Devic's disease, Erythroblastopenia, Evans         syndrome, Focal segmental glomerulosclerosis, Granulomatosis         with polyangiitis, Graves disease, Graves' ophthalmopathy,         Guillain-Barre syndrome, Hashimoto thyroiditis, idiopathic         thrombocytopenic purpura (ITP), IgA nephropathy, IgA-mediated         autoimmune diseases, IgG4-related disease, Inflammatory bowel         disease, Juvenile idiopathic arthritis, Multiple sclerosis,         Myasthenia gravis, myeloma, non-Hodgkin's lymphoma, Opsoclonus         myoclonus syndrome (OMS), Pemphigoid, Pemphigus, pemphigus         vulgaris, Pernicious anemia, polymyositis, Psoriasis, pure red         cell aplasia, Reactive arthritis, Rheumatoid arthritis,         Sarcoidosis, scleroderma, Sjögren syndrome, Systemic lupus         erythematosus, Thrombocytopenic purpura, Thrombotic         thrombocytopenic purpura, Type I diabetes, Ulcerative colitis,         Vasculitis, Vitiligo, and combinations thereof.         27. The method of paragraph 26, wherein the autoimmune disease         is multiple sclerosis or Crohn's disease.         28. The method of paragraph 27, wherein the autoimmune disease         is multiple sclerosis.         29. The method of paragraph 28, wherein the multiple sclerosis         is a relapsing form of multiple sclerosis.         30. The method of any one of paragraphs 1 to 29, wherein the one         or more immunosuppressive medications comprise a glucocorticoid,         cytostatic, antibody, drug acting on immunophilins, interferon,         opioid, TNF binding protein, mycophenolate, small biological         agent, small molecule, organic compound, or any combination         thereof.         31. The method of any one of paragraphs 1 to 30, wherein the one         or more immunosuppressive medications comprise a glucocorticoid,         cytostatic, antibody, drug acting on immunophilins, interferon,         opioid, TNF binding protein, mycophenolate, small biological         agent, small molecule, organic compound, A2aR antagonist, Akt         inhibitor, anti CD20, Anti-amyloidotic (AA) Agent, anti-CD37         protein therapeutic, anti-CTLA4 mAb, Anti-CXCR4, anti-huCD40         mAb, anti-LAG3 mAb, anti-PD-1 mAb, anti-PD-L1 agent, anti-PD-L1         agent, anti-PD-L1 mAb, anti-TGFb mAb, anti-TIGIT mAb, anti-TIM-3         mAb, Aurora kinase inhibitor, Bcl-2 Inhibitor, bifunctional         fusion protein targeting TGFb and PD-L1, bispecific anti-PD-1         and anti-LAG3 mAb, CD1d ligand, CD40 agonist, Complement C5a         inhibitor, CSF1R inhibitor, EZH2 inhibitor, FGFR3 inhibitor,         FGFR4 inhibitor, FGFrR3 inhibitor, glucocorticoid-induced tumor         necrosis factor receptor-related gene [GITR] agonist,         glutaminase inhibitor, Human monoclonal antibody against IL-12,         ICOS agonist, IDO1 inhibitor, IL2 mutein, IL2 receptor agonist,         MEK inhibitor, multitargeted receptor tyrosine kinase inhibitor,         neutrophil elastase inhibitor, Notch Inhibitor, p38 MAPK         inhibitor, PD-1 inhibitor, recombinant human Flt3L, ROCK         inhibitor, selective sphingosine-1-phosphate receptor modulator,         Src kinase inhibitor, TLR4 agonist, TLR9 agonist, abatacept         (e.g. ORENCIA), abrilumab, acalabrutinib, adalimumab,         adrenocorticotropic hormone, agatolimod sodium, AJM300,         aldesleukin, alefacept, alemtuzumab, alisertib, alvespimycin         hydrochloride, alvocidib, ambrisentan (e.g. LETAIRIS),         aminocamptothecin, amiselimod, anakinra, andecaliximab,         andrographolides (a botanical medicinal herb also known as         IB-MS), anifrolumab, antithymocyte Ig, apatinib, apelisib,         asparaginase, atacicept, atezolizumab, avelumab, azacitidine,         azathioprine, bafetinib, baminercept, baricitinib, basiliximab,         becatecarin, begelomab, belatacept, belimumab, bemcentinib,         bendamustine, bendamustine (e.g. bendamustine hydrochloride),         betalutin with lilotomab, bevacizumab, BIIB033, BIIB059,         BIIB061, bimekizumab, binimetinib, bleomycin, blinatumomab,         BNZ-1, bortezomib (e.g. VELCADE), brentuximab vedotin,         bryostatin 1, bucillamine, buparlisib, busulfan, canakinumab,         capecitabine, carboplatin, carfilzomib, carmustine, cediranib         maleate, cemiplimab, ceralifimod, cerdulatinib, certolizumab         (e.g. certolizumab pegol), cetuximab, chidamide, chlorambucil,         CHS-131, cilengitide, cirmtuzumab, cisplatin, cladribine,         clazakizumab, clemastine, clioquinol, corticosteroids,         cyclophosphamide, cyclosporine, cytarabine, cytotoxic         chemotherapy, daclizumab, dalfampridine (e.g. AMPYRA),         daprolizumab pegol, daratumumab, dasatinib, defactinib,         defibrotide, denosumab, dexamethasone, diacerein, dimethyl         fumarate, dinaciclib, diroximel fumarate (e.g. VUMERITY),         doxorubicin, doxorubicin (e.g. doxorubicin hydrochloride),         durvalumab, duvelisib, duvortuxizumab, eculizumab (e.g.         SOLIRIS), efalizumab, eftilagimod alpha, EK-12 (a neuropeptide         combination of metenkefalin and tridecactide), elezanumab,         elotuzumab (e.g. EMPLICITI), encorafenib, enfuvirtida (e.g.         FUZEON), entinostat, entospletinib, enzastaurin, epacadostat,         epirubicin, epratuzumab, eritoran tetrasodium, etanercept,         etoposide, etrolizumab, everolimus, evobrutinib, filgotinib,         fingolimod (e.g. fingolimod hydrochloride), firategrast,         fludarabine, fluorouracil, fontolizumab, forodesine         hydrochloride, fostamatinib, galunisertib, ganetespib,         ganitumab, gemcitabine, gemtuzumab ozogamicin, gerilimzumab,         glasdegib, glassia, glatiramer acetate, glembatumumab vedotin,         glesatinib, golimumab (e.g. SIMPONI), guadecitabine,         hydrocortisone, hydroxychloroquine sulfate, hydroxyurea,         ibritumomab tiuxetan, ibrutinib, ibudilast, idarubicin,         idebenone, idelalisib, ifosfamide, iguratimod, imatinib, imexon,         IMU-838, infliximab, inotuzumab ozogamicin, interferon alfa-2,         interferon beta-1a, interferon beta-1b, interferon gamma-1,         ipilimumab, irofulven, isatuximab, ispinesib, itacitinib,         ixazomib, lapatinib, laquinimod, laromustine, ld-aminopterin,         leflunomide, lenalidomide, lenvatinib, letrozole (e.g. FEMARA),         levamisole, levocabastine, lipoic acid, lirilumab, lonafamib,         lumiliximab, maraviroc (e.g. SELZENTRY), masitinib,         mavrilimumab, melphalan, mercaptopurine, methotrexate,         methoxsalen, methylprednisone, milatuzumab, mitoxantrone,         mizoribine, mocetinostat, monalizumab, mosunetuzumab, motesanib         diphosphate, moxetumomab pasudotox, muromonab-CD3, mycophenolate         mofetil (e.g. mycophenolate mofetil hydrochloride), mycophenolic         acid, namilumab, natalizumab, navitoclax, neihulizumab,         nerispirdine, neurovax, niraparib, nivolumab, obatoclax         mesylate, obinutuzumab, oblimersen sodium, ocrelizumab,         ofatumumab, olokizumab, opicinumab, oprelvekin, osimertinib,         otelixizumab, oxaliplatin, oxcarbazepine, ozanimod, paclitaxel,         pacritinib, palifermin, panobinostat, pazopanib, peficitinib,         pegfilgrastim (e.g. NEULASTA), peginterferon beta-1a,         pegsunercept (peg stnf-ri), pembrolizumab, pemetrexed,         penclomedine, pentostatin, perifosine, pevonedistat,         pexidartinib, picoplatin, pidilizumab, pivanex, pixantrone,         pleneva, plovamer acetate, polatuzumab vedotin, pomalidomide,         ponatinib, ponesimod, prednisone/prednisolone, pyroxamide,         R-411, ravulizimab-cwvz (e.g. (ULTOMIRIS), recombinant it-12,         relatlimab, rhigf-1, rhigm22, rigosertib, rilonacept, ritonavir         (e.g. NORVIR), rituximab, ruxolitinib, SAR442168/PRN2246,         sarilumab, secukinumab, selumetinib, simvastatin, sintilimab,         siplizumab, siponimod (e.g. MAYZENT), sirolimus (rapamycin),         sirukumab, sitravatinib, sonidegib, sorafenib, sotrastaurin         acetate, sunitinib, sunphenon epigallocatechin-gallate,         tabalumab, tacrolimus (e.g. tacrolimus anhydrous), talabostat         mesylate, talacotuzumab, tanespimycin,         tegafur/gimeracil/oteracil, temozolomide, temsirolimus,         tenalisib, terameprocol, teriflunomide, thalidomide, thiarabine,         thiotepa, tipifamib, tirabrutinib, tislelizumab, tivozanib,         tocilizumab, tofacitinib, TR-14035, tregalizumab, tremelimumab,         treosulfan, ublituximab, umbralisib, upadacitinib, urelumab,         ustekinumab, varlilumab, vatelizumab, vedolizumab, veliparib,         veltuzumab, venetoclax, vinblastine, vincristine, vinorelbine         ditartrate, visilizumab, vismodegib, vistusertib, voriconazole         (e.g. VFEND), vorinostat, vosaroxin, ziv-aflibercept, 2B3-201,         3PRGD2, 4SC-202, 506U78, 6,8-bis(benzylthio)octanoic acid,         68Ga-BNOTA-PRGD2, 852A, 89Zr-DFO-CZP, ABBV-257, ABL001, ABP 501,         ABP 710, ABP 798, ABT-122, ABT-199, ABT-263, ABT-348, ABT-494,         ABT-555, ABT-874, ABX-1431 HCl, ACP-196, ACP-319, ACT-128800,         ACY-1215, AD 452, Ad-P53, ADCT-301, ADCT-402, ADL5859, ADS-5102,         AFX-2, AGEN1884, AGEN2034, AGS67E, AIN457, AK106-001616, ALD518,         ALKS 8700, ALT-803, ALT-803, ALX-0061, ALXN1007, ALXN6000,         AMD3100, AMG 108, AMG 319, AMG 357, AMG 570, AMG 592, AMG 714,         AMG 719, AMG 827, AMP-110, AP1903, APL A12, AP0866, APX005M,         AQ4N, AR-42, ARN-6039, ARQ 531, ARRY-371797, ARRY-382,         ARRY-438162, ART-IO2, ART621, ASK8007, ASNO02, ASP015K, ASP1707,         ASP2408, ASP2409, ASP5094, AT-101, AT7519M, AT9283, ATA188,         ATN-103, ATX-MS-1467, AVL-292, AVP-923, AZD4573, AZD5672,         AZD5991, AZD6244, AZD6738, AZD9056, AZD9150, AZD9567, AZD9668,         B-701, BAF312, BAY1830839, BBI608, BCD-054, BCD-055, BCD-063,         BCD-089, BCD-100, BCD-132, BCD-145, BEZ235, BG00012, BG9924,         BGB-3111, BGB-A333, BGG492, BHT-3009, BI 655064, BI 695500, BI         695501, BI 836826, BI-1206, BIBR 796 BS, B1113017, B1113023,         BIIB057, B1113061, BIIL 284 BS, BLZ945, BMMNC, BMN 673,         BMS-247550, BMS-582949, BMS-817399, BMS-936558, BMS-936564,         BMS-945429, BMS-986104, BMS-986142, BMS-986156, BMS-986195,         BMS-986205, BMS-986213, BMS-986226, BMS-986251, BNC105P, BOW015,         BP1001, BT061, BTT-1023, C105, CAL-101, CAM-3001, CAT-8015,         CB-839, CBL0137, CC-1088, CC-115, CC-122, CC-292, CC100,         CCI-779, CCX 354-C, CDKI AT7519, CDP323, CDP6038, CDP870,         CDX-1127, CDX-301, CE-224535, CF101, CFZ533, CGP 77116, CH-1504,         CH-4051, CHR-5154, CHS-0214, CK-2017357, CLAG-M, CLR 131,         CMAB008, CMP-001, CNF2024 (BIIB021), CNM-Au8, CNTO 1275, CNTO         136, CNTO 148, CNTO 6785, CP-195543, CP-461, CpG 7909, CPI-1205,         CR6086, CRx-102, CS-0777, CS1002, CT-011, CT-1530, CT-P10,         CV301, CX-3543, DAC-HYP, DCDT2980S, DI-B4, DPA-714 FDG,         DS-3032b, DT2219ARL, DTRM-505, DTRM-555, DTRMWXHS-12, DWP422,         E6011, E7449, EK-12, ELND002, ENIA11, EOC202, ETBX-011, F81L10,         FBTA05, FEDAA1106 (BAY85-8101), FGF401, FKB327, FPA008, FR104,         FS118, FTY720, G100, GCS-100, GDC-0199, GDC-0853, GEH120714,         GLPG0259, GLPG0634, GNbAC1, GNKG168, GP2013, GP2015, GRN163L,         GS-1101, GS-5745, GS-9219, GS-9820, GS-9876, GS-9901,         GSK1223249, GSK1827771, GSK2018682, GSK21110183, GSK239512,         GSK2618960, GSK2831781, GSK2982772, GSK3117391, GSK3152314A,         GSK3196165, GSK3358699, GSK706769, GW-1000-02, GW274150,         GW406381, GW856553, GZ402668, HCD122, HE3286, HL2351, HL237,         hLL1-DOX (IMMU-115), HLX01, HM71224, HMPL-523, HSC835, HZT-501,         ICP-022, IDEC-C2B8, ILV-094, IMGN529, IMMU-114, IMO-2125,         INCAGN02385, INCB018424, INCB028050, INCB039110, INCB047986,         INCMGA00012, INNO-406, INT131, INT230-6, INVAC-1, IPI-145,         IPX056, ISF35, ISIS 104838, ITF2357, JCARH125, JHL1101, JNJ         38518168, JNJ-39758979, JNJ-40346527, JNJ-63723283, JS001,         JTE-051, JTX-2011, KB003, KD025, KPT-330, KW-2449, KW-2478,         KX2-391, L-778123, LAG525, LAM-002A, LBEC0101, LBH589, LFB-R603,         LMB-2, LX3305, LY2127399, LY2189102, LY2439821, LY3009104,         LY3090106, LY3300054, LY3321367, LY3337641, M2951, M7824, M923,         MBG453, MBP8298, MBS2320, MD1003, MDG013, MDV9300, MDX-1100,         MDX-1342, MDX-1411, ME-401, MEDI-522, MEDI-538, MEDI-551,         MEDI4920, MGA012, MGCD0103, MGD007, MIS416, MK-0873, MK-4280,         MK-4827, MK-8457, MK-8808, MK0359, MK0457, MK0752, MK0782,         MK0812, MK2206, MLN1202, MLTA3698A, MM-093, MN-122, MN-166,         monoclonal antibody M-T412, monoclonal antibody mono-dgA-RFB4,         MOR00208, MOR103, MORAb-022, MP-435, MP470, MRC375, MRG-106,         MS-533, MSB11022, MSC2490484A, MT-1303, MT-3724, MTIG7192A,         MTRX1011A, NBI-5788, NC-503, NI-0101, NI-071, NIS793, NKTR-214,         NNC 0141-0000-0100, NNC 0151-0000-0000, NNC0109-0012,         NNC0114-0000-0005, NNC0114-0006, NNC0142-0002, NNCO215-0384,         NNC109-0012, NOX-A12, NT-KO-003, NU100, OMB157, OMP-313M32,         ON01910 Na, ONO-2506P0, ONO-4641, ONTAK, OPB 31121, OSI-461,         OTS167IV, P1446A-05, PBF-509, PBRO6, PCI 32765, PCI-24781, PD         0360324, PDA001, PDR001, PF-04171327, PF-04236921, PF-04308515,         PF-04629991, PF-05280586, PF-06342674, PF-06410293, PF-06438179,         PF-06650833, PF-06651600, PF-06835375, PG-760564, PH-797804,         PLA-695, PLX3397, PLX5622, POL6326, PRO131921, PRO283698,         PRTX-100, PS-341, PTL201, R(+)XK469, R788, RAD001, RC18,         REGN1979, REGN3767, REGN2810, REGN4659, RFT5-SMPT-dgA, RG2077,         RGB-03, RGI-2001, RHB-104, RNS60, RO5045337, RO7123520, Rob 803,         RPC1063, RWJ-445380, S 55746, SAIT101, SAN-300, SAR245409,         SB-681323, SB683699, SBI-087, SC12267 (4SC-101), SCH 727965,         SC10-469, SD-101, SG2000, SGN-40, SHC014748M, SHR-1210, SHR0302,         SHR1020, SJG-136, SKI-O-703, SMP-114, SNS-032, SNS-062,         SNX-5422, SPARC1103 I, SPC2996, SSR150106, STA 5326 mesylate,         Sunpharma1505, SyB L-0501, Sym022, Sym023, SYN060, T-614, T0001,         TA-650, TAB08, TAK-715, TAK-783, TAK-901, TGR-1202, TH-302,         TL011, TMI-005, TMP001, TNFa Kinoid, TP-0903, TRU-015, TRU-016,         TSR-022, TSR-033, TSR-042, TXA127, VAY736, VP-16, VSN16R,         VX-509, VX-702, VX-745, VX15/2503, XCEL-MC-ALPHA, XL228, XL844,         XmAb13676, XmAb5574, XOMA 052, YRA-1909, Z102, ZEN003365, and         any combination thereof.         32. The method of paragraph 31, wherein the one or more         immunosuppressive medications comprise natalizumab, interferon         beta-1a, interferon beta-1b, glatiramer acetate, peginterferon         beta-1a, teriflunomide, fingolimod, dimethyl fumarate,         alemtuzumab, mitoxantrone, rituximab, daclizumab, ocrelizumab,         diroximel fumarate or siponimod, or any combination thereof.         33. The method of paragraph 32, wherein the one or more         immunosuppressive medications comprise natalizumab.         34. The method of paragraph 33, wherein the natalizumab is         administered via intravenous infusion.         35. The method of paragraph 33, wherein about 100 mg to about         500 mg of the natalizumab is administered.         36. The method of paragraph 35, wherein about 100 mg to about         500 mg of the natalizumab is administered in four weeks.         37. The method of paragraph 35 or 36, wherein about 100 mg to         about 500 mg of the natalizumab is administered via intravenous         infusion in four weeks.         38. The method of any one of paragraphs 1 to 37, wherein the         subject does not have one or more genetic variations associated         with a high risk of developing PML.         39. The method of any one of paragraphs 1 to 38, wherein the         genetic test comprises detecting one or more genetic variations         associated with a high risk of developing PML in a polynucleic         acid sample from the subject.         40. The method of paragraph 38 or 39, wherein the one or more         genetic variations comprise a point mutation, polymorphism,         single nucleotide polymorphism (SNP), single nucleotide         variation (SNV), translocation, insertion, deletion,         amplification, inversion, interstitial deletion, copy number         variation (CNV), structural variation (SV), loss of         heterozygosity, or any combination thereof.         41. The method of any one of paragraphs 38 to 40, wherein the         one or more genetic variations disrupt or modulate a         corresponding gene according to Tables 3, 6, 29, 31 and 48.         42. A method of treating a condition in a subject in need of         natalizumab therapy, comprising: administering a therapeutically         effective amount of natalizumab to the subject, wherein the         subject is identified as not having one or more genetic         variations that disrupt or modulate a corresponding gene         according to Tables 3, 6, 29, 31 and 48.         43. A method of reducing a risk of a subject developing         progressive multifocal leukoencephalopathy (PML) comprising         administering a therapeutically effective amount of natalizumab         to the subject, wherein the subject is identified as not having         one or more genetic variations that disrupt or modulate a         corresponding gene according to Tables 3, 6, 29, 31 and 48.         44. The method of paragraph 42 or 43, wherein the condition is         multiple sclerosis.         45. The method of paragraph 42 or 43, wherein the condition is         Crohn's disease.         46. A method of treating multiple sclerosis comprising         administering natalizumab to a subject with multiple sclerosis,         wherein the subject is identified as not having one or more         genetic variations that disrupt or modulate a corresponding gene         according to Tables 3, 6, 29, 31 and 48.         47. A method of treating Crohn's disease comprising         administering natalizumab to a subject with Crohn's disease,         wherein the subject is identified as not having one or more         genetic variations that disrupt or modulate a corresponding gene         according to Tables 3, 6, 29, 31 and 48.         48. A method of treating multiple sclerosis comprising     -   (a) testing a subject with multiple sclerosis for the presence         of one or more genetic variations that disrupt or modulate a         corresponding gene according to Tables 3, 6, 29, 31 and 48,     -   (b) determining that the subject does not have the one or more         genetic variations that disrupt or modulate a corresponding gene         according to Tables 3, 6, 29, 31 and 48, and     -   (c) administering natalizumab to the subject that was determined         not to have the one or more genetic variations that disrupt or         modulate a corresponding gene according to Tables 3, 6, 29, 31         and 48.         49. A method of treating Crohn's disease comprising     -   (a) testing a subject with Crohn's disease for the presence of         one or more genetic variations that disrupt or modulate a         corresponding gene according to Tables 3, 6, 29, 31 and 48,     -   (b) determining that the subject does not have the one or more         genetic variations that disrupt or modulate a corresponding gene         according to Tables 3, 6, 29, 31 and 48, and     -   (c) administering natalizumab to the subject that was determined         not to have the one or more genetic variations that disrupt or         modulate a corresponding gene according to Tables 3, 6, 29, 31         and 48.         50. A method of reducing a risk of a subject developing         progressive multifocal leukoencephalopathy (PML) comprising     -   (a) testing a subject for the presence of one or more genetic         variations that disrupt or modulate a corresponding gene         according to Tables 3, 6, 29, 31 and 48,     -   (b) determining that the subject has at least one of the one or         more genetic variations that disrupt or modulate a corresponding         gene according to Tables 3, 6, 29, 31 and 48, and     -   (c) advising against administering natalizumab to the subject         that was determined to have at least one of the one or more         genetic variations that disrupt or modulate a corresponding gene         according to Tables 3, 6, 29, 31 and 48.         51. The method of paragraph 50, wherein the subject has multiple         sclerosis.         52. The method of paragraph 50, wherein the subject has Crohn's         disease.         53. A method of treating multiple sclerosis comprising     -   (a) testing a subject with multiple sclerosis for the presence         of one or more genetic variations that disrupt or modulate a         corresponding gene according to Tables 3, 6, 29, 31 and 48,     -   (b) determining that the subject has at least one of the one or         more genetic variations that disrupt or modulate a corresponding         gene according to Tables 3, 6, 29, 31 and 48, and     -   (c) advising against administering natalizumab to the subject         that was determined to have at least one of the one or more         genetic variations that disrupt or modulate a corresponding gene         according to Tables 3, 6, 29, 31 and 48.         54. A method of treating Crohn's disease comprising     -   (a) testing a subject with Crohn's disease for the presence of         one or more genetic variations that disrupt or modulate a         corresponding gene according to Tables 3, 6, 29, 31 and 48,     -   (b) determining that the subject has at least one of the one or         more genetic variations that disrupt or modulate a corresponding         gene according to Tables 3, 6, 29, 31 and 48, and     -   (c) advising against administering natalizumab to the subject         that was determined to have at least one of the one or more         genetic variations that disrupt or modulate a corresponding gene         according to Tables 3, 6, 29, 31 and 48.         55. The method of any one of paragraphs 50 to 54, wherein the         advising comprises advising that administering natalizumab is         contraindicated.         56. The method of any one of paragraphs 50 to 55, wherein the         advising comprises advising that administering natalizumab         increases the risk of the subject developing progressive         multifocal leukoencephalopathy (PML).         57. The method of any one of paragraphs 50 to 56, wherein the         advising comprises advising that administering natalizumab is a         factor that increases the risk of the subject developing         progressive multifocal leukoencephalopathy (PML).         58. The method of any one of paragraphs 42 to 57, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene according to Table 13.         59. The method of any one of paragraphs 42 to 57, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene according to Table 14.         60. The method of any one of paragraphs 42 to 57, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene according to Table 15.         61. The method of any one of paragraphs 42 to 57, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene according to Table 16.         62. The method of any one of paragraphs 42 to 57, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene according to Table 17.         63. The method of any one of paragraphs 42 to 57, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene according to Table 18.         64. The method of any one of paragraphs 42 to 63, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene selected from the group consisting of ALG12, AP3B1, ASH1L,         ATL2, ATM, ATR, BACH1, BLM, CHD7, CLCN7, CR2, CX3CR1, DOCK2,         DOCKS, EHF, EPG5, FAS, FUK, GFI1, GOLGB1, GTPBP4, HIVEP1,         HIVEP2, HIVEP3, IFIH1, IGLL1, 1L10, IL12B, IL17F, ITK, ITSN2,         JAGN1, KITLG, LRBA, LYST, MALT1, MAVS, MCEE, NHEJ1, NOD2, NRIP1,         ORAI1, PGM3, PIK3CD, PLCG2, PNP, POLE, PRF1, RBCK1, RBFOX1,         RNASEL, RTEL1, SALL2, SHARPIN, SNAP29, STIM2, STXBP2, TAP1,         TBC1D16, TCIRG1, TICAM1, TMEM173, TNFRSF10A, TTC7A, VPS13B, and         combinations thereof.         65. The method of any one of paragraphs 42 to 63, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene selected from the group consisting of ACD, ADGRL2, AIRE,         ATG5, ATG7, BLK, BRD4, C3, C7, CBA, CSB, C9, CAMLG, CCBE1, CCZ1,         CD22, CD36, CD37, CD5, CD72, CFH, CFHR1, CFHR2, CFHR3, CFHR4,         CFHR5, CFTR, CHD2, CLEC16A, CLPB, COPA, CTC1, DNAJC21, EGF,         ERCC6L2, FAT4, FCER2, HERCS, HERC6, ICAM1, IFI35, IFIT1, IFIT3,         IL4, ITSN1, KMT2D, KRAS, LRRK2, MASP2, MBL2, MCM5, MDC1, MFN2,         MLH1, MMP9, MOGS, MON1A, MON1B, MSH2, MSHS, MX1, MX2, MYSM1,         NBAS, NCF1, NCF2, NCF4, NFATS, NLRP2, NLRX1, NOD1, OAS1, OAS2,         OAS3, ORC4, PARN, PEPD, PINK1, PLAU, PLAUR, PLCG1, PLD1,         PLEKHM1, PLK1, PLXNB1, PRRC2A, RABSA, RABSB, RAD50, RANBP2,         RELA, RLTPR, RNF125, RPSA, RSAD2, SAMD9, SAMD9L, SERPINA1,         SERPINB2, SMARCAL1, SMURF2, SRP54, TBC1D17, TCN2, TEK, TFPI,         TMC8, TP53AIP1, TRAF3IP2, USB1, USP3, VEGFA, WASHC5, WRAP53, and         XAF1.         66. The method of any one of paragraphs 42 to 64, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene selected from the group consisting of PLCG2, RBCK1, EPG5,         IL17F, SHARPIN, PRF1, JAGN1, TAP1, POLE, LRBA, EHF, IL12B, ATL2,         NHEJ1, LYST, HIVEP1, AP3B1, TNFRSF10A, PIK3CD, PNP, MCEE, DOCK2,         ALG12, and combinations thereof.         67. The method of any one of paragraphs 42 to 64, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene selected from the group consisting of PLCG2, IFIH1, TCIRG1,         IGLL1, MAVS, SHARPIN, CHD7, CX3CR1, LRBA, HIVEP3, RNASEL, and         combinations thereof.         68. The method of any one of paragraphs 42 to 64, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene selected from the group consisting of SHARPIN, RTEL1, PGM3,         TMEM173, CLCN7, MAVS, ORAI1, RBFOX1, MALT1, GFI1, DOCK2, ATM,         SNAP29, TICAM1, GTPBP4, BACH1, STXBP2, FAS, GOLGB1, FUK, IL10,         ITK, STIM2, ASH1L, TBC1D16, LYST, SALL2, CHD7, BLM, NOD2, IGLL1,         TTC7A, KITLG, ATR, ATM, CR2, HIVEP2, ITSN2, DOCKS, VPS13B,         NRIP1, and combinations thereof.         69. The method of any one of paragraphs 42 to 64, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene selected from the group consisting of SHARPIN, IFIH1,         PLCG2, CHD7, and combinations thereof.         70. The method of any one of paragraphs 42 to 64, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene selected from the group consisting of PLCG2, POLE, LRBA,         EPG5, SHARPIN, and combinations thereof.         71. The method of any one of paragraphs 42 to 64, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene selected from the group consisting of PKHD1, LY9, CFHR2,         NQO2, AIRE, TCIRG1, ATM, MDC1, PRAM1, FCN2, STXBP2, PLCG2, TAP1,         GFI1, IGLL1, MCM5, IFIH1, FCN3 and SERPINA1.         72. The method of any one of paragraphs 42 to 64, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene selected from the group consisting of of LY9, PKHD1, AIRE,         CFHR2, NQO2, IGLL1, PRAM1, MDC1, FCN2, STXBP2, TCIRG1 and PLCG2.         73. The method of any one of paragraphs 42 to 64, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene selected from the group consisting of LIG1, MCM5, GFI1,         IFIH1, IGLL1, ATM, TAP1, FCN3, LRBA and SERPINA1.         74. The method of any one of paragraphs 42 to 64, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene selected from the group consisting of TAP1, GFI1, IGLL1,         MCM5, IFIH1, FCN3, SERPINA1.         75. The method of any one of paragraphs 42 to 64, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene selected from the group consisting of PKHD1, LY9, CFHR2,         NQO2, AIRE, IGLL1, TCIRG1, ATM, MDC1, PRAM1, FCN2, STXBP2 and         PLCG2.         76. The method of any one of paragraphs 42 to 64, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene selected from the group consisting of LY9, LIG1, PKHD1,         AIRE, GFI1, CFHR2, NQO2, PRAM1, CSB, DNASE1L3, PLCG2, HIVEP3 and         TCIRG1. 77. The method of any one of paragraphs 42 to 64,         wherein the testing comprises testing the subject for the         presence of one or more genetic variations that disrupt or         modulate a corresponding gene selected from the group consisting         of PRAM1, HIVEP3 and TCIRG1.         78. The method of any one of paragraphs 42 to 64, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene selected from the group consisting of LY9, LIG1, PKHD1,         AIRE, GFI1, CFHR2, NQO2, C8B, DNASE1L3 and PLCG2.         79. The method of any one of paragraphs 42 to 64, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene selected from the group consisting of IGLL1, MDC1, STXBP2,         PRAM1, ATM, FCN2, IGLL1, MCM5, IFIH1, TAP1, PLCG2, FCN3, DNER,         SERPINA1 and LRBA.         80. The method of any one of paragraphs 42 to 64, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene selected from the group consisting of PRAM1, ATM, TAP1,         PLCG2, FCN3, DNER, SERPINA1 and LRBA.         81. The method of any one of paragraphs 42 to 64, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene selected from the group consisting of IGLL1, MDC1, STXBP2,         FCN2, IGLL1, MCM5 and IFIH1.         82. The method of any one of paragraphs 42 to 64, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene selected from the group consisting of AIRE, ATM, C8B,         CFHR2, DNASE1L3, DNER, FCN2, FCN3, GFI1, HIVEP3, IFIH1, IGLL1,         LIG1, LRBA, LY9, MCM5, MDC1, NQO2, PKHD1, PLCG2, PRAM1,         SERPINA1, STXBP2, TAP1 and TCIRG1.         83. The method of any one of paragraphs 42 to 64, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene selected from the group consisting of AIRE, ATM, C8B,         CFHR2, DNASE1L3, DNER, FCN2, FCN3, GFI1, HIVEP3, IGLL1, LIG1,         LRBA, LY9, MCM5, MDC1, NQO2, PKHD1, PRAM1, SERPINA1, and TAN.         84. The method of any one of paragraphs 42 to 64, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene selected from the group consisting of FCN2, LY9 and PRAM1.         85. The method of any one of paragraphs 42 to 64, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene selected from the group consisting of PLCG2, RBCK1, EPG5,         IL17F, SHARPIN, PRF1, JAGN1, TAP1, POLE, LRBA, EHF, IL12B, ATL2,         NHEJ1, LYST, HIVEP1, AP3B1, TNFRSF10A, PIK3CD, PNP, MCEE, DOCK2,         ALG12, FCN2, LY9 and PRAM1.         86. The method of any one of paragraphs 42 to 64, wherein the         testing comprises testing the subject for the presence of one or         more genetic variations that disrupt or modulate a corresponding         gene selected from the group consisting of PLCG2, CHD7, IFIH1,         AP3B1, EPG5, PIK3CD, LRBA, SHARPIN, and combinations thereof.         87. The method of any one of paragraphs 42 to 86, wherein the         subject is identified as not having a high risk of developing         progressive multifocal leukoencephalopathy (PML) by a genetic         test.         88. The method of any one of paragraphs 48 to 87, wherein the         testing comprises assaying a polynucleic acid sample from the         subject for the one or more genetic variations.         89. The method of any one of paragraphs 38 to 88, wherein the         one or more genetic variations result in a loss of function of         the corresponding gene.         90. The method of any one of paragraphs 41 to 89, wherein the         corresponding gene comprises a gene selected from the group         consisting of gene numbers (GNs) GN1-GN765.         91. The method of paragraph 90, wherein the corresponding gene         comprises a gene selected from the group consisting of gene         numbers (GNs) GN1-GN156 in Table 3.         92. The method of paragraph 90, wherein the corresponding gene         comprises a gene selected from the group consisting of gene         numbers (GNs) GN 2-4, 6, 8-13, 23-28, 31-39, 41-47, 51-57,         59-62, 64-67, 69, 72-75, 89, 92-95, 98-105, 107-120, 123-128,         130, 131, 133, 134, 136, 138-142, 145, 147, 148, 157-174,         176-179, 181-205, 207-239, 241, 243-307, 309-315, 317-353,         355-369, 371-435, 437, 439-482 and 484-490 in Table 6.         93. The method of paragraph 90, wherein the corresponding gene         comprises a gene selected from the group consisting of gene         numbers (GNs) GN491-GN492 in Table 29.         94. The method of paragraph 90, wherein the corresponding gene         comprises a gene selected from the group consisting of gene         numbers (GNs) GN493-GN762 in Table 31.         95. The method of paragraph 90, wherein the corresponding gene         comprises a gene selected from the group consisting of gene         numbers (GNs) GN763-GN765 in Table 48.         96. The method of paragraph 90, wherein the corresponding gene         comprises a gene selected from Tables 34-40, 42, 45A, 45B, 45C,         48, 50A, 50B and 51-62.         97. The method of paragraph 90, wherein the corresponding gene         comprises a gene selected from the group consisting of PLCG2,         RBCK1, EPG5, IL17F, SHARPIN, PRF1, JAGN1, TAP1, POLE, LRBA, EHF,         IL12B, ATL2, NHEJ1, LYST, HIVEP1, AP3B1, TNFRSF10A, PIK3CD, PNP,         MCEE, DOCK2 and ALG12.         98. The method of any one of paragraphs 38 to 97, wherein the         one or more genetic variations are encoded by a sequence with at         least 60%, at least 70%, at least 80%, at least 90%, at least         95%, or at least 99% sequence identity to SEQ ID NOs 1-172 or         SRN1-SRN363, with 100% sequence identity to SEQ ID NOs         1000-1329, or with at least 80% and less than 100% sequence         identity to GN1-GN490, or complements thereof.         99. The method of any one of paragraphs 38 to 97, wherein the         one or more genetic variations are encoded by a sequence with at         least 60%, at least 70%, at least 80%, at least 90%, at least         95%, or at least 99% sequence identity to SEQ ID NOs 1-172,         2200-2203 or SRN1-SRN366, with 100% sequence identity to SEQ ID         NOs 1000-1329, 3000-3274, or with at least 80% and less than         100% sequence identity to GN1-GN765, or complements thereof.         100. The method of any one of paragraphs 38 to 97, wherein the         one or more genetic variations are encoded by a sequence with at         least 60%, at least 70%, at least 80%, at least 90%, at least         95%, or at least 99% sequence identity to SEQ ID NOs 2200-2203         or SRN364-SRN366, with 100% sequence identity to SEQ ID NOs         3000-3274, or with at least 80% and less than 100% sequence         identity to GN491-GN765, or complements thereof.         101. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation encoded by a CNV with at         least 60%, at least 70%, at least 80%, at least 90%, at least         95%, or at least 99% sequence identity to SEQ ID NOs 1-172, or         complements thereof.         102. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation encoded by a CNV with at         least 60%, at least 70%, at least 80%, at least 90%, at least         95%, or at least 99% sequence identity to SEQ ID NOs 2200-2203,         or complements thereof.         103. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation encoded by a CNV         sub-region (SRN) with at least 60%, at least 70%, at least 80%,         at least 90%, at least 95%, or at least 99% sequence identity to         SRN1-SRN363, or complements thereof.         104. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation encoded by a CNV         sub-region (SRN) with at least 60%, at least 70%, at least 80%,         at least 90%, at least 95%, or at least 99% sequence identity to         SRN364-SRN366, or complements thereof.         105. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation encoded by a single         nucleotide variation (SNV) with a sequence of any one of SEQ ID         NOs: 1000-1329, or complements thereof.         106. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation encoded by a single         nucleotide variation (SNV) with a sequence of any one of SEQ ID         NOs: 3000-3274, or complements thereof.         107. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation encoded by a sequence         with at least 80% and less than 100% sequence identity to         GN1-GN490, or complements thereof.         108. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation encoded by a sequence         with at least 80% and less than 100% sequence identity to         GN491-GN765, or complements thereof.         109. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation encoded by a single         nucleotide variation (SNV) with a sequence of any one of SEQ ID         NO: 1000, 1001, 1002, 1009, 1010, 1011, 1012, 1014, 1016, 1017,         1019, 1020, 1028, 1032, 1033, 1034, 1035, 1036, 1037, 1040,         1041, 1043, 1051, 1054, 1056, 1057, 1058, 1059, 1061, 1062,         1063, 1066, 1068, 1069, 1070, 1071, 1073, 1074, 1075, 1076,         1077, 1078, 1080, 1082, 1084, 1090, 1092, 1098, 1099, 1100,         1101, 1104, 1107, 1114, 1116, 1118, 1121, 1122, 1123, 1125,         1126, 1127, 1128, 1129, 1130, 1131, 1133, 1135, 1136, 1137,         1138, 1142, 1146, 1147, 1148, 1150, 1152, 1154, 1157, 1160,         1161, 1165, 1166, 1167, 1168, 1169, 1171, 1174, 1175, 1176,         1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1193, 1194,         1200, 1201, 1202, 1203, 1204, 1208, 1219, 1220, 1221, 1222,         1226, 1227, 1228, 1229, 1230, 1231, 1232, 1235, 1239, 1247,         1248, 1249, 1250, 1251, 1252, 1254, 1255, 1256, 1259, 1260,         1261, 1263, 1264, 1266, 1267, 1273, 1278, 1279, 1283, 1284,         1286, 1287, 1289, 1290, 1291, 1299, 1300, 1301, 1304, 1311, 1327         or 1328, or complements thereof.         110. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation encoded by a single         nucleotide variation (SNV) with a sequence of any one of SEQ ID         NO: 3000-3274, or complements thereof.         111. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation encoded by a single         nucleotide variation (SNV) with a sequence of any one of SEQ ID         NO: 3300-3351, 3400-3467 or 3500-3526.         112. The method of paragraph 109, wherein the one or more         genetic variations comprise a genetic variation encoded by a         single nucleotide variation (SNV) with a sequence of any one of         SEQ ID NO: 1011, 1020, 1028, 1032, 1034, 1035, 1036, 1040, 1056,         1069, 1073, 1077, 1101, 1114, 1123, 1125, 1126, 1127, 1135,         1142, 1146, 1147, 1148, 1152, 1154, 1157, 1167, 1174, 1184,         1193, 1194, 1203, 1208, 1221, 1222, 1229, 1235, 1252, 1255,         1256, 1259, 1260, 1261, 1263, 1273, 1278, 1279, 1284, 1287,         1289, 1299 or 1311, or complements thereof.         113. The method of paragraph 109, wherein the one or more         genetic variations comprise a genetic variation encoded by a         single nucleotide variation (SNV) with a sequence of any one of         SEQ ID NO: 1000, 1001, 1002, 1009, 1010, 1012, 1014, 1016, 1017,         1019, 1033, 1037, 1041, 1043, 1051, 1054, 1057, 1058, 1059,         1061, 1062, 1063, 1066, 1068, 1070, 1071, 1074, 1075, 1076,         1078, 1080, 1082, 1084, 1090, 1092, 1098, 1099, 1100, 1104,         1107, 1116, 1118, 1121, 1122, 1128, 1129, 1130, 1131, 1133,         1136, 1137, 1138, 1146, 1147, 1150, 1152, 1160, 1161, 1165,         1166, 1168, 1169, 1171, 1175, 1176, 1177, 1178, 1179, 1180,         1181, 1182, 1183, 1200, 1201, 1202, 1204, 1219, 1220, 1226,         1227, 1228, 1230, 1231, 1232, 1239, 1247, 1248, 1249, 1250,         1251, 1252, 1254, 1264, 1266, 1267, 1278, 1279, 1283, 1286,         1290, 1291, 1300, 1301, 1304, 1327 or 1328, or complements         thereof.         114. The method of paragraph 98, wherein the one or more genetic         variations comprise a genetic variation selected from the group         consisting of chr16:81942175 A>G, chr2:163136505 C>G,         chr11:67818269 G>A, chr22:23917192 G>T, chr20:3846397 C>T,         chr8:145154222, G>A chr8:61654298 T>A, chr3:39323163 A>C,         chr4:151199080 G>A, chr1:42047208 C>G, chr2:163124051 C>T,         chr1:182554557 C>T, chr8:145154824 A>C, chr20:62305450 C>T,         chr22:23915745 G>A, chr6:83884161 C>G, chr11:108202772 G>T,         chr5:138856923 C>T, chr16:1510535 C>T, chr20:3843027 C>A,         chr12:122064788 G>GT, chr16:7714909 C>T, chr18:56401523 C>T,         chr1:92946625 G>C, chr5:169081453 G>C, chr11:108117787 C>T,         chr22:21235389 A>G, chr19:4817657 C>T, chr10:1060218 G>A,         chr21:30698953 T>G, chr9:304628 G>A, chr19:7712287 G>C,         chr10:90771767 G>A, chr3:121415370 T>C, chr16:70503095 A>G,         chr1:206945738 C>T, chr5:156593120 C>T, chr4:27019452 C>T,         chr1:155317682 C>T, chr17:77926526 C>T, chr1:235840495 G>T,         chr14:21993359 G>A, chr8:61757805 C>T, chr15:91306241 G>A,         chr16:50741791 C>T, chr22:23915583 T>C, chr2:47205921 C>T,         chr12:88900891 C>A, chr3:142281353 C>G, chr11:108123551 C>T,         chr1:207641950 C>T, chr6:143092151 T>C, chr2:24431184 C>T,         chr2:24432937 C>T, chr9:312134 G>A, chr8:100205255 G>A,         chr21:16339852 T>C, and any combination thereof, wherein         chromosome positions of the one or more genetic variations are         defined with respect to UCSC hg19.         115. The method of paragraph 114, wherein the one or more         genetic variations comprise a genetic variation selected from         the group consisting of chr16:81942175 A>G, chr2:163136505 C>G,         chr11:67818269 G>A, chr22:23917192 G>T, chr20:3846397 C>T,         chr8:145154222, G>A chr8:61654298 T>A, chr3:39323163 A>C,         chr4:151199080 G>A, chr1:42047208 C>G, chr2:163124051 C>T,         chr1:182554557 C>T, and any combination thereof, wherein         chromosome positions of the one or more genetic variations are         defined with respect to UCSC hg19.         116. The method of paragraph 114, wherein the one or more         genetic variations comprise a genetic variation selected from         the group consisting of chr8:145154824 A>C, chr20:62305450 C>T,         chr22:23915745 G>A, chr6:83884161 C>G, chr11:108202772 G>T,         chr5:138856923 C>T, chr16:1510535 C>T, chr20:3843027 C>A,         chr12:122064788 G>GT, chr16:7714909 C>T, chr18:56401523 C>T,         chr1:92946625 G>C, chr5:169081453 G>C, chr11:108117787 C>T,         chr22:21235389 A>G, chr19:4817657 C>T, chr10:1060218 G>A,         chr21:30698953 T>G, chr9:304628 G>A, chr19:7712287 G>C,         chr10:90771767 G>A, chr3:121415370 T>C, chr16:70503095 A>G,         chr1:206945738 C>T, chr5:156593120 C>T, chr4:27019452 C>T,         chr1:155317682 C>T, chr17:77926526 C>T, chr1:235840495 G>T,         chr14:21993359 G>A, chr8:61757805 C>T, chr15:91306241 G>A,         chr16:50741791 C>T, chr22:23915583 T>C, chr2:47205921 C>T,         chr12:88900891 C>A, chr3:142281353 C>G, chr11:108123551 C>T,         chr1:207641950 C>T, chr6:143092151 T>C, chr2:24431184 C>T,         chr2:24432937 C>T, chr9:312134 G>A, chr8:100205255 G>A,         chr21:16339852 T>C, and any combination thereof, wherein         chromosome positions of the one or more genetic variations are         defined with respect to UCSC hg19.         117. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation selected from the group         consisting of chr1:196759282, C>T, chr4:126412634, C>G,         chr10:75673748, A>C, chr6:30675830, T>A, chr6:30680721, G>A,         chr12:56385915, GGGA>G, chr18:57103126, G>A, chr3:171321023,         C>T, chr1:59131311, G>T, chr22:31008867, T>C, chr2:74690378,         C>T, chr17:7592168, C>G, chr2:74690039, G>A, chr12:113448288,         A>G, chr17:76130947, G>T, chr2:15674686, T>C, chr2:15607842,         T>C, chr14:94847262, T>A, chr4:126412154, G>A, chr22:37271882,         T>C, chr20:44640959, G>A, chr17:8138569, C>G, chr12:113357237,         G>C, chr12:113357209, G>A, chr11:60893235, C>T, chr12:113357442,         G>A, chr5:40964852, A>C, chr14:35497285, T>C, chr19:55494157,         G>A, and any combination thereof, wherein chromosome positions         of the one or more genetic variations are defined with respect         to UCSC hg19.         118. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation selected from the group         consisting of chr11:72145307, C>G, chr7:30491421, G>T,         chr6:30673403, A>G, chr19:44153248, T>C, chr17:43555253, A>G,         chr2:188349523, A>G, chr1:57409459, C>A, chr4:126241248, C>G,         chr5:39311336, A>T, chr17:76129619, C>T, chr4:110929301, T>C,         chr3:11402163, G>A, chr16:67694044, C>T, chr19:10395141, G>A,         chr6:106740989, T>C, chr1:183532364, T>A, chr22:35806756, G>A,         chr4:110865044, G>C, chr4:110864533, C>T, chr4:126238090, G>T,         chr4:110932508, C>A, chr6:31605016, T>C, chr7:92733766, C>A,         chr18:29645930, A>T, and any combination thereof, wherein         chromosome positions of the one or more genetic variations are         defined with respect to UCSC hg19.         119. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation selected from the group         consisting of chr21:45708278, G>A, chr11:108106443, T>A,         chr1:57409459, C>A, chr1:196918605, A>G, chr3:58191230, G>T,         chr2:230579019, G>A, chr9:137779251, G>A, chr1:27699670, AG>A,         chr1:92946625, G>C, chr1:42047208, C>G, chr2:163136505, C>G,         chr22:23915583, T>C, chr22:23915745, G>A, chr19:48643270, C>T,         chr4:151793903, T>C, chr1:160769595, AG>A, chr22:35806756, G>A,         chr6:30673359, T>G, chr6:3015818, G>A, chr6:51798908, C>T,         chr16:81942175, A>G, chr19:8564523, T>G, chr14:94847262, T>A,         chr19:7712287, G>C, chr6:32814942, C>T, chr6:32816772, C>A and         chr11:67818269, G>A, wherein chromosome positions of the one or         more genetic variations are defined with respect to UCSC hg19.         120. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation selected from the group         consisting of chr21:45708278, G>A, chr11:108106443, T>A,         chr1:57409459, C>A, chr1:196918605, A>G, chr3:58191230, G>T,         chr2:230579019, G>A, chr9:137779251, G>A, chr1:27699670, AG>A,         chr1:92946625, G>C, chr1:42047208, C>G, chr22:23915583, T>C,         chr19:48643270, C>T, chr4:151793903, T>C, chr1:160769595, AG>A,         chr22:35806756, G>A, chr6:30673359, T>G, chr6:3015818, G>A,         chr6:51798908, C>T, chr19:8564523, T>G, chr14:94847262, T>A,         chr6:32814942, C>T and chr6:32816772, C>A, wherein chromosome         positions of the one or more genetic variations are defined with         respect to UCSC hg19.         121. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation selected from the group         consisting of chr22:23915745, G>A, chr6:30673359, T>G,         chr19:7712287, G>C, chr9:137779251, G>A, chr22:23915583, T>C,         chr22:35806756, G>A and chr2:163136505, C>G, wherein chromosome         positions of the one or more genetic variations are defined with         respect to UCSC hg19.         122. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation selected from the group         consisting of chr19:8564523, T>G, chr11:108106443, T>A,         chr6:32816772, C>A, chr6:32814942, C>T, chr16:81942175, A>G,         chr1:27699670, AG>A, chr2:230579019, G>A, chr14:94847262, T>A         and chr4:151793903, T>C, wherein chromosome positions of the one         or more genetic variations are defined with respect to UCSC         hg19.         123. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation selected from the group         consisting of chr22:23915745, G>A, chr6:30673359, T>G,         chr19:7712287, G>C, chr19:8564523, T>G, chr11:108106443, T>A,         chr9:137779251, G>A, chr22:23915583, T>C, chr22:35806756, G>A,         chr2:163136505, C>G, chr6:32816772, C>A, chr6:32814942, C>T,         chr16:81942175, A>G, chr1:27699670, AG>A, chr2:230579019, G>A,         chr14:94847262 and T>A, chr4:151793903, T>C, wherein chromosome         positions of the one or more genetic variations are defined with         respect to UCSC hg19.         124. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation selected from the group         consisting of chr1:160769595, AG>A, chr19:48643270, C>T,         chr6:51798908, C>T, chr21-45708278-G-A, chr1:92946625, G>C,         chr1:196918605, A>G, chr6:3015818, G>A, chr1:57409459, C>A,         chr3:58191230, G>T and chr16:81942175, A>G, wherein chromosome         positions of the one or more genetic variations are defined with         respect to UCSC hg19.         125. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation selected from the group         consisting of chr19:8564523, T>G, chr1:42047208, C>G and         chr11:67818269, G>A, wherein chromosome positions of the one or         more genetic variations are defined with respect to UCSC hg19.         126. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation selected from the group         consisting of chr1:160769595, AG>A, chr19:48643270, C>T,         chr6:51798908, C>T, chr21-45708278-G-A, chr1:92946625, G>C,         chr1:196918605, A>G, chr6:3015818, G>A, chr19:8564523, T>G,         chr1:57409459, C>A, chr3:58191230, G>T, chr16:81942175, A>G,         chr1:42047208, C>G and chr11:67818269, G>A, wherein chromosome         positions of the one or more genetic variations are defined with         respect to UCSC hg19.         127. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation selected from the group         consisting of chr6:51798908, C>T, chr1:160769595, AG>A,         chr1:196918605, A>G, chr6:3015818, G>A, chr21-45708278-G-A,         chr22:23915745, G>A, chr11:67818269, G>A, chr11:108106443, T>A,         chr6:30673359, T>G, chr19:8564523, T>G, chr9:137779251, G>A,         chr19:7712287, G>C and chr16:81942175, A>G, wherein chromosome         positions of the one or more genetic variations are defined with         respect to UCSC hg19.         128. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation selected from the group         consisting of chr6:32816772, C>A, chr6:32814942, C>T,         chr1:92946625, G>C, chr22:23915583, T>C, chr22:35806756, G>A,         chr2:163136505, C>G, chr1:27699670, AG>A and chr14:94847262,         T>A, wherein chromosome positions of the one or more genetic         variations are defined with respect to UCSC hg19.         129. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation selected from the group         consisting of chr6:51798908, C>T, chr1:160769595, AG>A,         chr1:196918605, A>G, chr6:3015818, G>A, chr21-45708278-G-A,         chr22:23915745, G>A, chr11:67818269, G>A, chr11:108106443, T>A,         chr6:30673359, T>G, chr19:8564523, T>G, chr9:137779251, G>A,         chr19:7712287, G>C, chr16:81942175, A>G, chr6:32816772, C>A,         chr6:32814942, C>T, chr1:92946625, G>C, chr22:23915583, T>C,         chr22:35806756, G>A, chr2:163136505, C>G, chr1:27699670, AG>A         and chr14:94847262, T>A, wherein chromosome positions of the one         or more genetic variations are defined with respect to UCSC         hg19.         130. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation selected from the group         consisting of chr1:160769595, AG>A, chr6:51798908, C>T,         chr21-45708278-G-A, chr1:196918605, A>G, chr6:3015818, G>A,         chr22:23915745, G>A, chr19:8564523, T>G, chr6:30673359, T>G,         chr9:137779251, G>A, chr19:7712287, G>C, chr11:67818269, G>A and         chr16:81942175, A>G, wherein chromosome positions of the one or         more genetic variations are defined with respect to UCSC hg19.         131. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation selected from the group         consisting of chr19:48643270, C>T, chr22:35806756, G>A,         chr1:92946625, G>C, chr2:163136505, C>G, chr22:23915583, T>C,         chr11:108106443, T>A, chr6:32814942, C>T, chr6:32816772, C>A,         chr1:27699670, AG>A, chr4:151793903, T>C and chr14:94847262,         T>A, wherein chromosome positions of the one or more genetic         variations are defined with respect to UCSC hg19.         132. The method of paragraph 99, wherein the one or more genetic         variations comprise a genetic variation selected from the group         consisting of chr1:160769595, AG>A, chr6:51798908, C>T,         chr21-45708278-G-A, chr1:196918605, A>G, chr6:3015818, G>A,         chr22:23915745, G>A, chr19:8564523, T>G, chr6:30673359, T>G,         chr9:137779251, G>A, chr19:7712287, G>C, chr11:67818269, G>A,         chr16:81942175, A>G, chr19:48643270, C>T, chr22:35806756, G>A,         chr1:92946625, G>C, chr2:163136505, C>G, chr22:23915583, T>C,         chr11:108106443, T>A, chr6:32814942, C>T, chr6:32816772, C>A,         chr1:27699670, AG>A, chr4:151793903, T>C and chr14:94847262,         T>A, wherein chromosome positions of the one or more genetic         variations are defined with respect to UCSC hg19.         133. The method of paragraph 99, wherein the one or more genetic         variations do not comprise a genetic variation of         chr2:163136505, C>G, wherein chromosome positions of the one or         more genetic variations are defined with respect to UCSC hg19.         134. The method of paragraph 99, wherein the one or more genetic         variations do not comprise a genetic variation of         chr22:23915745, G>A, wherein chromosome positions of the one or         more genetic variations are defined with respect to UCSC hg19.         135. The method of paragraph 99, wherein the one or more genetic         variations do not comprise a genetic variation of         chr16:81942175, A>G, wherein chromosome positions of the one or         more genetic variations are defined with respect to UCSC hg19.         136. The method of paragraph 99, wherein the one or more genetic         variations do not comprise a genetic variation of chr19:7712287,         G>C, wherein chromosome positions of the one or more genetic         variations are defined with respect to UCSC hg19.         137. The method of paragraph 99, wherein the one or more genetic         variations do not comprise a genetic variation of         chr11:67818269, G>A, wherein chromosome positions of the one or         more genetic variations are defined with respect to UCSC hg19.         138. The method of paragraph 99, wherein the one or more genetic         variations do not comprise a genetic variation of         chr2:163136505, C>G; chr22:23915745, G>A; chr16:81942175, A>G;         chr19:7712287, G>C; and chr11:67818269, G>A, wherein chromosome         positions of the one or more genetic variations are defined with         respect to UCSC hg19.         139. The method of any one of paragraphs 105 or 109-138, wherein         the SNV is a heterozygous SNV.         140. The method of any one of paragraphs 105 or 109-138, wherein         the SNV is a homozygous SNV.         141. The method of paragraph 98, wherein the one or more genetic         variations comprise a pair of single nucleotide variations         (SNVs), wherein the pair of SNVs are encoded by any one of SEQ         ID NO pairs: 1003 and 1004, 1003 and 1005, 1006 and 1007, 1024         and 1025, 1030 and 1031, 1047 and 1048, 1049 and 1050, 1063 and         1064, 1063 and 1065, 1063 and 1066, 1075 and 1076, 1091 and         1093, 1091 and 1096, 1093 and 1095, 1094 and 1097, 1098 and         1099, 1098 and 1100, 1099 and 1100, 1102 and 1103, 1104 and         1106, 1104 and 1107, 1104 and 1108, 1104 and 1109, 1104 and         1110, 1104 and 1111, 1104 and 1112, 1110 and 1111, 1112 and         1113, 1119 and 1120, 1124 and 1125, 1124 and 1126, 1125 and         1126, 1140 and 1141, 1142 and 1144, 1146 and 1151, 1147 and         1148, 1147 and 1149, 1153 and 1146, 1153 and 1147, 1155 and         1156, 1160 and 1161, 1165 and 1166, 1186 and 1187, 1188 and         1193, 1189 and 1193, 1191 and 1192, 1191 and 1193, 1191 and         1195, 1192 and 1193, 1192 and 1195, 1196 and 1197, 1206 and         1207, 1210 and 1218, 1211 and 1213, 1212 and 1213, 1213 and         1215, 1213 and 1216, 1213 and 1217, 1233 and 1238, 1242 and         1243, 1245 and 1246, 1263 and 1260, 1269 and 1279, 1270 and         1279, 1270 and 1282, 1271 and 1279, 1274 and 1279, 1278 and         1279, 1278 and 1281, 1279 and 1280, 1279 and 1281, 1279 and         1282, 1292 and 1293, 1296 and 1297, 1305 and 1314, 1306 and         1310, 1313 and 1321 or 1315 and 1322, or complements thereof.         142. The method of paragraph 98, wherein the one or more genetic         variations comprise a genetic variation encoded by a CNV with at         least 60%, at least 70%, at least 80%, at least 90%, at least         95%, or at least 99% sequence identity to any one of SEQ ID NOs         157, 2, 140, 65, 26, 14 or 45, or complements thereof.         143. The method of paragraph 142, wherein the one or more         genetic variations comprise a genetic variation encoded by a CNV         with at least 60%, at least 70%, at least 80%, at least 90%, at         least 95%, or at least 99% sequence identity to any one of SEQ         ID NOs 2, 140, 65, 26, 14 or 45, or complements thereof.         144. The method of paragraph 142, wherein the one or more         genetic variations comprise a genetic variation encoded by a CNV         with at least 60%, at least 70%, at least 80%, at least 90%, at         least 95%, or at least 99% sequence identity to SEQ ID NO 157,         or a complement thereof 145. The method of paragraph 98, wherein         the one or more genetic variations comprise a CNV-SNV pair         comprising a CNV and a single nucleotide variation (SNV),         wherein the SNV of the CNV-SNV pair is encoded by any one of SEQ         ID NO pairs: 146 and 1301, 85 and 1173, 58 and 1107, 58 and         1104, 91 and 1199, 103 and 1225, 103 and 1086 or 41 and 1223, or         complements thereof.         146. The method of any one of paragraphs 38 to 145, wherein the         one or more genetic variations comprise a genetic variation         selected from the group consisting of: chr8:145154222 G>A,         chr2:163136505 C>G, chr16:81942175 A>G, chr8:61654298 T>A, and         combinations thereof.         147. The method of any one of paragraphs 38 to 145, wherein the         one or more genetic variations disrupt or modulate one or more         of the following genes: PLCG2, POLE, LRBA, EPG5 and SHARPIN.         148. The method of any one of paragraphs 38 to 145, wherein the         one or more genetic variations disrupt or modulate one or more         of the following genes: PLCG2, CHD7, IFIH1, AP3B1, EPG5, PIK3CD,         LRBA and SHARPIN.         149. The method of any one of paragraphs 41 to 148, wherein the         corresponding gene encodes a transcript with a sequence that has         at least 60%, at least 70%, at least 80%, at least 90%, at least         95%, or at least 99% sequence identity to any one of SEQ ID NOs         173-455, 1500-2177, 2204-2215, 2300-2893, or complements         thereof.         150. The method of paragraph 149, wherein the corresponding gene         encodes a transcript with a sequence that has at least 60%, at         least 70%, at least 80%, at least 90%, at least 95%, or at least         99% sequence identity to any one of SEQ ID NOs 173-455, or         complements thereof.         151. The method of paragraph 149, wherein the corresponding gene         encodes a transcript with a sequence that has at least 60%, at         least 70%, at least 80%, at least 90%, at least 95%, or at least         99% sequence identity to any one of SEQ ID NOs 1500-2177, or         complements thereof.         152. The method of paragraph 149, wherein the corresponding gene         encodes a transcript with a sequence that has at least 60%, at         least 70%, at least 80%, at least 90%, at least 95%, or at least         99% sequence identity to any one of SEQ ID NOs 2204-2215, or         complements thereof.         153. The method of paragraph 149, wherein the corresponding gene         encodes a transcript with a sequence that has at least 60%, at         least 70%, at least 80%, at least 90%, at least 95%, or at least         99% sequence identity to any one of SEQ ID NOs 2300-2893, or         complements thereof.         154. The method of any one of paragraphs 38 to 151, wherein the         one or more genetic variations comprise 2 or 3 or 4 or 5 or more         genetic variations.         155. The method of paragraph 154, wherein the one or more         genetic variations comprise 10 or more genetic variations.         156. The method of paragraph 154, wherein the one or more         genetic variations comprise 20 or more genetic variations.         157. The method of paragraph 154, wherein the one or more         genetic variations comprise 50 or more genetic variations.         158. The method of any one of paragraphs 1 to 41 and 87 to 157,         wherein the genetic test or the testing comprises microarray         analysis, PCR, sequencing, nucleic acid hybridization, or any         combination thereof.         159. The method of paragraph 158, wherein the genetic test or         the testing comprises microarray analysis selected from the         group consisting of a Comparative Genomic Hybridization (CGH)         array analysis and an SNP array analysis.         160. The method of paragraph 158 or 159, wherein the genetic         test or the testing comprises sequencing, wherein the sequencing         is selected from the group consisting of Massively Parallel         Signature Sequencing (MPSS), polony sequencing, 454         pyrosequencing, Illumina sequencing, Illumina (Solexa)         sequencing using 10× Genomics library preparation, SOLiD         sequencing, ion semiconductor sequencing, DNA nanoball         sequencing, heliscope single molecule sequencing, single         molecule real time (SMRT) sequencing, RNAP sequencing, Nanopore         DNA sequencing, sequencing by hybridization, and microfluidic         Sanger sequencing.         161. The method of any one of paragraphs 1 to 41 and 87 to 160,         wherein the genetic test or the testing comprises analyzing a         whole genome of the subject.         162. The method of any one of paragraphs 1 to 41 and 87 to 161,         wherein the genetic test or the testing comprises analyzing a         whole exome of the subject.         163. The method of any one of paragraphs 1 to 41 and 87 to 160,         wherein the genetic test or the testing comprises analyzing         nucleic acid information that has already been obtained for a         whole genome or a whole exome of the subject 164. The method of         paragraph 163, wherein the nucleic acid information is obtained         from an in silico analysis.         165. The method of any one of paragraphs 1 to 164, wherein the         subject is a human subject.         166. The method of any one of paragraphs 39 to 41 and 88 to 165,         wherein the polynucleic acid sample comprises a polynucleic acid         from blood, saliva, urine, serum, tears, skin, tissue, or hair         of the subject.         167. The method of any one of paragraphs 1 to 166, wherein the         method further comprises treating the subject with an agent that         reduces a viral load in the subject.         168. The method of paragraph 167, wherein the immunosuppressive         agent is administered after the viral load is reduced.         169. The method of paragraph 167 or 168, wherein the viral load         is a JCV viral load.         170. The method of any one of paragraphs 167 to 169, wherein the         agent that reduces the viral load is an agent that targets JCV.         171. The method of any one of paragraphs 1 to 170, wherein the         method further comprises analyzing for a presence of JCV in a         biological sample from the subject.         172. The method of paragraph 171, wherein the analyzing for a         presence of JCV comprises contacting a JCV detection reagent to         the biological sample.         173. The method of paragraph 172, wherein the JCV detection         reagent is selected from the group consisting of an anti-JCV         antibody, a JCV specific primer, and combinations thereof.         174. A method of treating a condition in a subject in need         thereof, comprising: administering     -   (a) a therapeutically effective amount of one or more         immunosuppressive medications to the subject, and     -   (b) one or more agents that reduce a viral load in the subject,         wherein the subject is identified as not having a high risk of         developing progressive multifocal leukoencephalopathy (PML) by a         genetic test         175. A method of treating a condition in a subject in need         thereof, comprising:     -   (a) analyzing a polynucleic acid sample from the subject for one         or more genetic variations that disrupt or modulate a gene of         GN1-GN765, wherein a genetic variation of the one or more         genetic variations that disrupt or modulate a gene of GN1-GN765         is not present in the polynucleic acid sample;     -   (b) identifying the subject as not having a high risk of         developing PML;     -   (c) administering a therapeutically effective amount of one or         more immunosuppressive medications to the subject.         176. A method of identifying a subject as having a risk of         developing PML, comprising:     -   (a) analyzing a polynucleic acid sample from the subject for one         or more genetic variations that disrupt or modulate a gene of         GN1-GN765, wherein a genetic variation of the one or more         genetic variations that disrupt or modulate a gene of GN1-GN765         is not present in the polynucleic acid sample;     -   (b) identifying the subject as not having a high risk of         developing PML.         177. A method of identifying a subject as having a risk of         developing progressive multifocal leukoencephalopathy (PML)         comprising     -   (a) obtaining a genetic test result from a polynucleic acid         sample from a subject, and     -   (b) identifying the subject as having a risk of developing PML         based on the genetic test result; wherein the subject is         immunosuppressed.         178. A method of monitoring a subject as having a risk of         developing progressive multifocal leukoencephalopathy (PML)         comprising     -   (a) obtaining a genetic test result from a polynucleic acid         sample from a subject, and     -   (b) identifying the subject as having an increased risk of         developing PML based on the genetic test result;         wherein the subject is immunosuppressed.         179. The method of paragraph 178, wherein the subject is on an         immunosuppressive therapy.         180. A method of identifying a subject as having a risk of         developing progressive multifocal leukoencephalopathy (PML)         comprising     -   (a) detecting one or more genetic variations that disrupt or         modulate a gene of GN1-GN765 in a polynucleic acid sample from a         subject, and     -   (b) identifying the subject as having a risk of developing PML;         wherein the subject is immunosuppressed.         181. A method of identifying a subject as having a risk of         developing progressive multifocal leukoencephalopathy (PML)         comprising:     -   (a) analyzing a polynucleic acid sample from the subject for one         or more genetic variations that disrupt or modulate a gene of         GN1-GN765, wherein a genetic variation of the one or more         genetic variations that disrupt or modulate a gene of GN1-GN765         is present in the polynucleic acid sample;     -   (b) identifying the subject as having a high risk of developing         PML;         wherein the subject is immunosuppressed.         182. The method of any one of paragraphs 177 to 181, wherein the         subject has HIV.         183. The method of any one of paragraphs 175 to 182, wherein the         condition is a cancer, an organ transplant, or an autoimmune         disease.         184. The method of paragraph 183, wherein the condition is an         autoimmune disease.         185. The method of paragraph 184, wherein the autoimmune disease         is selected from the group consisting of Addison disease,         Behcet's Disease, Inflammatory bowel disease, Celiac         disease—sprue (gluten-sensitive enteropathy), Crohn's disease,         Dermatomyositis, Focal segmental glomerulosclerosis, Graves         disease, Hashimoto thyroiditis, Multiple sclerosis, Myasthenia         gravis, Pemphigus, Pemphigoid, Aplastic anemia, Pernicious         anemia, Autoimmune hemolytic anemia, Erythroblastopenia,         Thrombocytopenic purpura, Evans syndrome, Vasculitis,         Granulomatosis with polyangiitis, Chronic inflammatory         demyelinating polyneuropathy, Guillain-Barre syndrome, Anti-NMDA         receptor encephalitis, Devic's disease, Autoimmune pancreatitis,         Opsoclonus myoclonus syndrome, IgG4-related disease, Psoriasis,         Reactive arthritis, Rheumatoid arthritis, Juvenile idiopathic         arthritis, Sarcoidosis, Sjögren syndrome, Systemic lupus         erythematosus, Type I diabetes, Vitiligo, or Ulcerative colitis.         186. The method of paragraph 185, wherein the autoimmune disease         is multiple sclerosis or Crohn's disease.         187. The method of any one of paragraphs 175 to 186, wherein the         one or more immunosuppressive medications comprise a         glucocorticoid, cytostatic, antibody, drug acting on         immunophilins, interferon, opioid, TNF binding protein,         mycophenolate, small biological agent, small molecule, organic         compound, or any combination thereof.         188. The method of any one of paragraphs 175 to 187, wherein the         one or more immunosuppressive medications comprise a interferon         beta-1a, interferon beta-1b, glatiramer acetate, peginterferon         beta-1a, teriflunomide, fingolimod, dimethyl fumarate,         alemtuzumab, mitoxantrone, rituximab, natalizumab, daclizumab,         ocrelizumab, diroximel fumarate, siponimod or any combination         thereof.         189. The method of paragraph 188, wherein the one or more         immunosuppressive medications comprise natalizumab.         190. The method of any one of paragraphs 175 to 189, wherein the         one or more genetic variations comprise a point mutation,         polymorphism, single nucleotide polymorphisms (SNP), single         nucleotide variation (SNV), translocation, insertion, deletion,         amplification, inversion, interstitial deletion, copy number         variation (CNV), structural variation (SV), loss of         heterozygosity, or any combination thereof.         191. The method of any one of paragraphs 175 to 190, wherein the         one or more genetic variations result in a loss of function of         the corresponding gene.         192. The method of any one of paragraphs 175 to 191, wherein the         corresponding gene comprises a gene selected from the group         consisting of gene numbers (GNs) GN1-GN765.         193. The method of any one of paragraphs 175 to 191, wherein the         gene comprises a gene selected from the group consisting of gene         numbers (GNs) GN1-GN156 in Table 3.         194. The method of any one of paragraphs 175 to 191, wherein the         gene comprises a gene selected from the group consisting of gene         numbers (GNs) GN 2-4, 6, 8-13, 23-28, 31-39, 41-47, 51-57,         59-62, 64-67, 69, 72-75, 89, 92-95, 98-105, 107-120, 123-128,         130, 131, 133, 134, 136, 138-142, 145, 147, 148, 157-174,         176-179, 181-205, 207-239, 241, 243-307, 309-315, 317-353,         355-369, 371-435, 437, 439-482 and 484-490 in Table 6.         195. The method of any one of paragraphs 175 to 191, wherein the         gene comprises a gene selected from the group consisting of gene         numbers (GNs) GN491-GN492 in Table 29.         196. The method of any one of paragraphs 175 to 191, wherein the         gene comprises a gene selected from the group consisting of gene         numbers (GNs) GN493-GN762 in Table 31.         197. The method of any one of paragraphs 175 to 191, wherein the         gene comprises a gene selected from the group consisting of gene         numbers (GNs) GN763-GN765 in Table 48.         198. The method of any one of paragraphs 175 to 191, wherein the         corresponding gene comprises a gene selected from Tables 34-40,         and 42.         199. The method of any one of paragraphs 175 to 191, wherein the         gene comprises a gene selected from the group consisting of         PLCG2, RBCK1, EPG5, IL17F, SHARPIN, PRF1, JAGN1, TAN, POLE,         LRBA, EHF, IL12B, ATL2, NHEJ1, LYST, HIVEP1, AP3B1, TNFRSF10A,         PIK3CD, PNP, MCEE, DOCK2 and ALG12.         200. The method of any one of paragraphs 175 to 191, wherein the         one or more genetic variations comprise a genetic variation         encoded by a sequence with at least 60%, at least 70%, at least         80%, at least 90%, at least 95%, or at least 99% sequence         identity to SEQ ID NOs 1-172, 2200-2203, or SRN1-SRN366, with         100% sequence identity to SEQ ID NOs 1000-1329, 3000-3274, or         with at least 80% and less than 100% sequence identity to         GN1-GN765, or complements thereof.         201. The method of any one of paragraphs 175 to 191, wherein the         one or more genetic variations are encoded by a sequence with at         least 60%, at least 70%, at least 80%, at least 90%, at least         95%, or at least 99% sequence identity to SEQ ID NOs 2200-2203,         or SRN364-SRN366, with 100% sequence identity to SEQ ID NOs         3000-3274, or with at least 80% and less than 100% sequence         identity to GN491-GN765, or complements thereof.         202. The method of paragraph 200, wherein the one or more         genetic variations comprise a genetic variation encoded by a CNV         with at least 60%, at least 70%, at least 80%, at least 90%, at         least 95%, or at least 99% sequence identity to SEQ ID NOs         1-172, or complements thereof.         203. The method of paragraph 200, wherein the one or more         genetic variations comprise a genetic variation encoded by a CNV         with at least 60%, at least 70%, at least 80%, at least 90%, at         least 95%, or at least 99% sequence identity to SEQ ID NOs         2200-2203, or complements thereof.         204. The method of paragraph 200, wherein the one or more         genetic variations comprise a genetic variation encoded by a CNV         sub-region (SRN) with at least 60%, at least 70%, at least 80%,         at least 90%, at least 95%, or at least 99% sequence identity to         SRN1-SRN363, or complements thereof.         205. The method of paragraph 200, wherein the one or more         genetic variations comprise a genetic variation encoded by a CNV         sub-region (SRN) with at least 60%, at least 70%, at least 80%,         at least 90%, at least 95%, or at least 99% sequence identity to         SRN364-SRN366, or complements thereof.         206. The method of paragraph 200, wherein the one or more         genetic variations are encoded by a single nucleotide variation         (SNV) with a sequence of any one of SEQ ID NOs: 1000-1329, or         complements thereof.         207. The method of paragraph 200, wherein the one or more         genetic variations comprise a genetic variation encoded by a         single nucleotide variation (SNV) with a sequence of any one of         SEQ ID NOs: 3000-3274, or complements thereof.         208. The method of paragraph 200, wherein the one or more         genetic variations comprise a genetic variation encoded by a         sequence with at least 80% and less than 100% sequence identity         to GN1-GN490, or complements thereof.         209. The method of paragraph 200, wherein the one or more         genetic variations comprise a genetic variation encoded by a         sequence with at least 80% and less than 100% sequence identity         to GN491-GN765, or complements thereof.         210. The method of paragraph 200, wherein the one or more         genetic variations comprise a genetic variation encoded by a         single nucleotide variation (SNV) with a sequence of any one of         SEQ ID NO: 1000, 1001, 1002, 1009, 1010, 1011, 1012, 1014, 1016,         1017, 1019, 1020, 1028, 1032, 1033, 1034, 1035, 1036, 1037,         1040, 1041, 1043, 1051, 1054, 1056, 1057, 1058, 1059, 1061,         1062, 1063, 1066, 1068, 1069, 1070, 1071, 1073, 1074, 1075,         1076, 1077, 1078, 1080, 1082, 1084, 1090, 1092, 1098, 1099,         1100, 1101, 1104, 1107, 1114, 1116, 1118, 1121, 1122, 1123,         1125, 1126, 1127, 1128, 1129, 1130, 1131, 1133, 1135, 1136,         1137, 1138, 1142, 1146, 1147, 1148, 1150, 1152, 1154, 1157,         1160, 1161, 1165, 1166, 1167, 1168, 1169, 1171, 1174, 1175,         1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1193,         1194, 1200, 1201, 1202, 1203, 1204, 1208, 1219, 1220, 1221,         1222, 1226, 1227, 1228, 1229, 1230, 1231, 1232, 1235, 1239,         1247, 1248, 1249, 1250, 1251, 1252, 1254, 1255, 1256, 1259,         1260, 1261, 1263, 1264, 1266, 1267, 1273, 1278, 1279, 1283,         1284, 1286, 1287, 1289, 1290, 1291, 1299, 1300, 1301, 1304,         1311, 1327 or 1328, or complements thereof.         211. The method of paragraph 210, wherein the one or more         genetic variations comprise a genetic variation encoded by a         single nucleotide variation (SNV) with a sequence of any one of         SEQ ID NO: 1011, 1020, 1028, 1032, 1034, 1035, 1036, 1040, 1056,         1069, 1073, 1077, 1101, 1114, 1123, 1125, 1126, 1127, 1135,         1142, 1146, 1147, 1148, 1152, 1154, 1157, 1167, 1174, 1184,         1193, 1194, 1203, 1208, 1221, 1222, 1229, 1235, 1252, 1255,         1256, 1259, 1260, 1261, 1263, 1273, 1278, 1279, 1284, 1287,         1289, 1299 or 1311, or complements thereof.         212. The method of paragraph 210, wherein the one or more         genetic variations comprise a genetic variation encoded by a         single nucleotide variation (SNV) with a sequence of any one of         SEQ ID NO: 1000, 1001, 1002, 1009, 1010, 1012, 1014, 1016, 1017,         1019, 1033, 1037, 1041, 1043, 1051, 1054, 1057, 1058, 1059,         1061, 1062, 1063, 1066, 1068, 1070, 1071, 1074, 1075, 1076,         1078, 1080, 1082, 1084, 1090, 1092, 1098, 1099, 1100, 1104,         1107, 1116, 1118, 1121, 1122, 1128, 1129, 1130, 1131, 1133,         1136, 1137, 1138, 1146, 1147, 1150, 1152, 1160, 1161, 1165,         1166, 1168, 1169, 1171, 1175, 1176, 1177, 1178, 1179, 1180,         1181, 1182, 1183, 1200, 1201, 1202, 1204, 1219, 1220, 1226,         1227, 1228, 1230, 1231, 1232, 1239, 1247, 1248, 1249, 1250,         1251, 1252, 1254, 1264, 1266, 1267, 1278, 1279, 1283, 1286,         1290, 1291, 1300, 1301, 1304, 1327 or 1328, or complements         thereof.         213. The method of any one of paragraphs 175 to 191, wherein the         one or more genetic variations comprise a genetic variation         selected from the group consisting of chr16:81942175 A>G,         chr2:163136505 C>G, chr11:67818269 G>A, chr22:23917192 G>T,         chr20:3846397 C>T, chr8:145154222, G>A chr8:61654298 T>A,         chr3:39323163 A>C, chr4:151199080 G>A, chr1:42047208 C>G,         chr2:163124051 C>T, chr1:182554557 C>T, chr8:145154824 A>C,         chr20:62305450 C>T, chr22:23915745 G>A, chr6:83884161 C>G,         chr11:108202772 G>T, chr5:138856923 C>T, chr16:1510535 C>T,         chr20:3843027 C>A, chr12:122064788 G>GT, chr16:7714909 C>T,         chr18:56401523 C>T, chr1:92946625 G>C, chr5:169081453 G>C,         chr11:108117787 C>T, chr22:21235389 A>G, chr19:4817657 C>T,         chr10:1060218 G>A, chr21:30698953 T>G, chr9:304628 G>A,         chr19:7712287 G>C, chr10:90771767 G>A, chr3:121415370 T>C,         chr16:70503095 A>G, chr1:206945738 C>T, chr5:156593120 C>T,         chr4:27019452 C>T, chr1:155317682 C>T, chr17:77926526 C>T,         chr1:235840495 G>T, chr14:21993359 G>A, chr8:61757805 C>T,         chr15:91306241 G>A, chr16:50741791 C>T, chr22:23915583 T>C,         chr2:47205921 C>T, chr12:88900891 C>A, chr3:142281353 C>G,         chr11:108123551 C>T, chr1:207641950 C>T, chr6:143092151 T>C,         chr2:24431184 C>T, chr2:24432937 C>T, chr9:312134 G>A,         chr8:100205255 G>A, chr21:16339852 T>C, and any combination         thereof, wherein chromosome positions of the one or more genetic         variations are defined with respect to UCSC hg19.         214. The method of paragraph 213, wherein the one or more         genetic variations comprise a genetic variation selected from         the group consisting of chr16:81942175 A>G, chr2:163136505 C>G,         chr11:67818269 G>A, chr22:23917192 G>T, chr20:3846397 C>T,         chr8:145154222, G>A chr8:61654298 T>A, chr3:39323163 A>C,         chr4:151199080 G>A, chr1:42047208 C>G, chr2:163124051 C>T,         chr1:182554557 C>T, and any combination thereof, wherein         chromosome positions of the one or more genetic variations are         defined with respect to UCSC hg19.         215. The method of paragraph 213, wherein the one or more         genetic variations comprise a genetic variation selected from         the group consisting of chr8:145154824 A>C, chr20:62305450 C>T,         chr22:23915745 G>A, chr6:83884161 C>G, chr11:108202772 G>T,         chr5:138856923 C>T, chr16:1510535 C>T, chr20:3843027 C>A,         chr12:122064788 G>GT, chr16:7714909 C>T, chr18:56401523 C>T,         chr1:92946625 G>C, chr5:169081453 G>C, chr11:108117787 C>T,         chr22:21235389 A>G, chr19:4817657 C>T, chr10:1060218 G>A,         chr21:30698953 T>G, chr9:304628 G>A, chr19:7712287 G>C,         chr10:90771767 G>A, chr3:121415370 T>C, chr16:70503095 A>G,         chr1:206945738 C>T, chr5:156593120 C>T, chr4:27019452 C>T,         chr1:155317682 C>T, chr17:77926526 C>T, chr1:235840495 G>T,         chr14:21993359 G>A, chr8:61757805 C>T, chr15:91306241 G>A,         chr16:50741791 C>T, chr22:23915583 T>C, chr2:47205921 C>T,         chr12:88900891 C>A, chr3:142281353 C>G, chr11:108123551 C>T,         chr1:207641950 C>T, chr6:143092151 T>C, chr2:24431184 C>T,         chr2:24432937 C>T, chr9:312134 G>A, chr8:100205255 G>A,         chr21:16339852 T>C, and any combination thereof, wherein         chromosome positions of the one or more genetic variations are         defined with respect to UCSC hg19.         216. The method of any one of paragraphs 175 to 191, wherein the         one or more genetic variations comprise a genetic variation         selected from the group consisting of chr1:196759282, C>T,         chr4:126412634, C>G, chr10:75673748, A>C, chr6:30675830, T>A,         chr6:30680721, G>A, chr12:56385915, GGGA>G, chr18:57103126, G>A,         chr3:171321023, C>T, chr1:59131311, G>T, chr22:31008867, T>C,         chr2:74690378, C>T, chr17:7592168, C>G, chr2:74690039, G>A,         chr12:113448288, A>G, chr17:76130947, G>T, chr2:15674686, T>C,         chr2:15607842, T>C, chr14:94847262, T>A, chr4:126412154, G>A,         chr22:37271882, T>C, chr20:44640959, G>A, chr17:8138569, C>G,         chr12:113357237, G>C, chr12:113357209, G>A, chr11:60893235, C>T,         chr12:113357442, G>A, chr5:40964852, A>C, chr14:35497285, T>C,         chr19:55494157, G>A, and any combination thereof, wherein         chromosome positions of the one or more genetic variations are         defined with respect to UCSC hg19.         217. The method of any one of paragraphs 175 to 191, wherein the         one or more genetic variations comprise a genetic variation         selected from the group consisting of chr11:72145307, C>G,         chr7:30491421, G>T, chr6:30673403, A>G, chr19:44153248, T>C,         chr17:43555253, A>G, chr2:188349523, A>G, chr1:57409459, C>A,         chr4:126241248, C>G, chr5:39311336, A>T, chr17:76129619, C>T,         chr4:110929301, T>C, chr3:11402163, G>A, chr16:67694044, C>T,         chr19:10395141, G>A, chr6:106740989, T>C, chr1:183532364, T>A,         chr22:35806756, G>A, chr4:110865044, G>C, chr4:110864533, C>T,         chr4:126238090, G>T, chr4:110932508, C>A, chr6:31605016, T>C,         chr7:92733766, C>A, chr18:29645930, A>T, and any combination         thereof, wherein chromosome positions of the one or more genetic         variations are defined with respect to UCSC hg19.         218. The method of any one of paragraphs 175 to 191, wherein the         one or more genetic variations comprise a genetic variation         selected from the group consisting of chr21:45708278, G>A,         chr11:108106443, T>A, chr1:57409459, C>A, chr1:196918605, A>G,         chr3:58191230, G>T, chr2:230579019, G>A, chr9:137779251, G>A,         chr1:27699670, AG>A, chr1:92946625, G>C, chr1:42047208, C>G,         chr2:163136505, C>G, chr22:23915583, T>C, chr22:23915745, G>A,         chr19:48643270, C>T, chr4:151793903, T>C, chr1:160769595, AG>A,         chr22:35806756, G>A, chr6:30673359, T>G, chr6:3015818, G>A,         chr6:51798908, C>T, chr16:81942175, A>G, chr19:8564523, T>G,         chr14:94847262, T>A, chr19:7712287, G>C, chr6:32814942, C>T,         chr6:32816772, C>A and chr11:67818269, G>A, wherein chromosome         positions of the one or more genetic variations are defined with         respect to UCSC hg19.         219. The method of any one of paragraphs 175 to 191, wherein the         one or more genetic variations comprise a genetic variation         selected from the group consisting of chr22:23915745, G>A,         chr6:30673359, T>G, chr19:7712287, G>C, chr9:137779251, G>A,         chr22:23915583, T>C, chr22:35806756, G>A and chr2:163136505,         C>G, wherein chromosome positions of the one or more genetic         variations are defined with respect to UCSC hg19. 220. In some         embodiments, the one or more genetic variations comprise a         genetic variation selected from the group consisting of         chr19:8564523, T>G, chr11:108106443, T>A, chr6:32816772, C>A,         chr6:32814942, C>T, chr16:81942175, A>G, chr1:27699670, AG>A,         chr2:230579019, G>A, chr14:94847262, T>A and chr4:151793903,         T>C, wherein chromosome positions of the one or more genetic         variations are defined with respect to UCSC hg19.         221. The method of any one of paragraphs 175 to 191, wherein the         one or more genetic variations comprise a genetic variation         selected from the group consisting of chr22:23915745, G>A,         chr6:30673359, T>G, chr19:7712287, G>C, chr19:8564523, T>G,         chr11:108106443, T>A, chr9:137779251, G>A, chr22:23915583, T>C,         chr22:35806756, G>A, chr2:163136505, C>G, chr6:32816772, C>A,         chr6:32814942, C>T, chr16:81942175, A>G, chr1:27699670, AG>A,         chr2:230579019, G>A, chr14:94847262 and T>A, chr4:151793903,         T>C, wherein chromosome positions of the one or more genetic         variations are defined with respect to UCSC hg19.         222. The method of any one of paragraphs 175 to 191, wherein the         one or more genetic variations comprise a genetic variation         selected from the group consisting of chr1:160769595, AG>A,         chr19:48643270, C>T, chr6:51798908, C>T, chr21-45708278-G-A,         chr1:92946625, G>C, chr1:196918605, A>G, chr6:3015818, G>A,         chr1:57409459, C>A, chr3:58191230, G>T and chr16:81942175, A>G,         wherein chromosome positions of the one or more genetic         variations are defined with respect to UCSC hg19.         223. The method of any one of paragraphs 175 to 191, wherein the         one or more genetic variations comprise a genetic variation         selected from the group consisting of chr19:8564523, T>G,         chr1:42047208, C>G and chr11:67818269, G>A, wherein chromosome         positions of the one or more genetic variations are defined with         respect to UCSC hg19.         224. The method of any one of paragraphs 175 to 191, wherein the         one or more genetic variations comprise a genetic variation         selected from the group consisting of chr1:160769595, AG>A,         chr19:48643270, C>T, chr6:51798908, C>T, chr21-45708278-G-A,         chr1:92946625, G>C, chr1:196918605, A>G, chr6:3015818, G>A,         chr19:8564523, T>G, chr1:57409459, C>A, chr3:58191230, G>T,         chr16:81942175, A>G, chr1:42047208, C>G and chr11:67818269, G>A,         wherein chromosome positions of the one or more genetic         variations are defined with respect to UCSC hg19.         225. The method of any one of paragraphs 175 to 191, wherein the         one or more genetic variations comprise a genetic variation         selected from the group consisting of chr6:51798908, C>T,         chr1:160769595, AG>A, chr1:196918605, A>G, chr6:3015818, G>A,         chr21-45708278-G-A, chr22:23915745, G>A, chr11:67818269, G>A,         chr11:108106443, T>A, chr6:30673359, T>G, chr19:8564523, T>G,         chr9:137779251, G>A, chr19:7712287, G>C and chr16:81942175, A>G,         wherein chromosome positions of the one or more genetic         variations are defined with respect to UCSC hg19.         226. The method of any one of paragraphs 175 to 191, wherein the         one or more genetic variations comprise a genetic variation         selected from the group consisting of chr6:32816772, C>A,         chr6:32814942, C>T, chr1:92946625, G>C, chr22:23915583, T>C,         chr22:35806756, G>A, chr2:163136505, C>G, chr1:27699670, AG>A         and chr14:94847262, T>A, wherein chromosome positions of the one         or more genetic variations are defined with respect to UCSC         hg19.         227. The method of any one of paragraphs 175 to 191, wherein the         one or more genetic variations comprise a genetic variation         selected from the group consisting of chr6:51798908, C>T,         chr1:160769595, AG>A, chr1:196918605, A>G, chr6:3015818, G>A,         chr21-45708278-G-A, chr22:23915745, G>A, chr11:67818269, G>A,         chr11:108106443, T>A, chr6:30673359, T>G, chr19:8564523, T>G,         chr9:137779251, G>A, chr19:7712287, G>C, chr16:81942175, A>G,         chr6:32816772, C>A, chr6:32814942, C>T, chr1:92946625, G>C,         chr22:23915583, T>C, chr22:35806756, G>A, chr2:163136505, C>G,         chr1:27699670, AG>A and chr14:94847262, T>A, wherein chromosome         positions of the one or more genetic variations are defined with         respect to UCSC hg19.         228. The method of any one of paragraphs 175 to 191, wherein the         one or more genetic variations comprise a genetic variation         selected from the group consisting of chr1:160769595, AG>A,         chr6:51798908, C>T, chr21-45708278-G-A, chr1:196918605, A>G,         chr6:3015818, G>A, chr22:23915745, G>A, chr19:8564523, T>G,         chr6:30673359, T>G, chr9:137779251, G>A, chr19:7712287, G>C,         chr11:67818269, G>A and chr16:81942175, A>G, wherein chromosome         positions of the one or more genetic variations are defined with         respect to UCSC hg19.         229. The method of any one of paragraphs 175 to 191, wherein the         one or more genetic variations comprise a genetic variation         selected from the group consisting of chr19:48643270, C>T,         chr22:35806756, G>A, chr1:92946625, G>C, chr2:163136505, C>G,         chr22:23915583, T>C, chr11:108106443, T>A, chr6:32814942, C>T,         chr6:32816772, C>A, chr1:27699670, AG>A, chr4:151793903, T>C and         chr14:94847262, T>A, wherein chromosome positions of the one or         more genetic variations are defined with respect to UCSC hg19.         230. The method of any one of paragraphs 175 to 191, wherein the         one or more genetic variations comprise a genetic variation         selected from the group consisting of chr1:160769595, AG>A,         chr6:51798908, C>T, chr21-45708278-G-A, chr1:196918605, A>G,         chr6:3015818, G>A, chr22:23915745, G>A, chr19:8564523, T>G,         chr6:30673359, T>G, chr9:137779251, G>A, chr19:7712287, G>C,         chr11:67818269, G>A, chr16:81942175, A>G, chr19:48643270, C>T,         chr22:35806756, G>A, chr1:92946625, G>C, chr2:163136505, C>G,         chr22:23915583, T>C, chr11:108106443, T>A, chr6:32814942, C>T,         chr6:32816772, C>A, chr1:27699670, AG>A, chr4:151793903, T>C and         chr14:94847262, T>A, wherein chromosome positions of the one or         more genetic variations are defined with respect to UCSC hg19.         231. The method of any one of paragraphs 175 to 191, wherein the         one or more genetic variations do not comprise a genetic         variation of chr2:163136505, C>G, wherein chromosome positions         of the one or more genetic variations are defined with respect         to UCSC hg19.         232. The method of any one of paragraphs 175 to 191, wherein the         one or more genetic variations do not comprise a genetic         variation of chr22:23915745, G>A, wherein chromosome positions         of the one or more genetic variations are defined with respect         to UCSC hg19. 233. The method of any one of paragraphs 175 to         191, wherein the one or more genetic variations do not comprise         a genetic variation of chr16:81942175, A>G, wherein chromosome         positions of the one or more genetic variations are defined with         respect to UCSC hg19.         234. The method of any one of paragraphs 175 to 191, wherein the         one or more genetic variations do not comprise a genetic         variation of chr19:7712287, G>C, wherein chromosome positions of         the one or more genetic variations are defined with respect to         UCSC hg19.         235. The method of any one of paragraphs 175 to 191, wherein the         one or more genetic variations do not comprise a genetic         variation of chr11:67818269, G>A, wherein chromosome positions         of the one or more genetic variations are defined with respect         to UCSC hg19.         236. The method of any one of paragraphs 175 to 191, wherein the         one or more genetic variations do not comprise a genetic         variation of chr2:163136505, C>G; chr22:23915745, G>A;         chr16:81942175, A>G; chr19:7712287, G>C; and chr11:67818269,         G>A, wherein chromosome positions of the one or more genetic         variations are defined with respect to UCSC hg19.         237. The method of any one of paragraphs 200-215, wherein the         SNV is a heterozygous SNV.         238. The method of any one of paragraphs 200-215, wherein the         SNV is a homozygous SNV.         239. The method of any one of paragraphs 200-237, wherein the         one or more genetic variations comprise a pair of single         nucleotide variations (SNVs), wherein the pair of SNVs are         encoded by any one of SEQ ID NO pairs: 1003 and 1004, 1003 and         1005, 1006 and 1007, 1024 and 1025, 1030 and 1031, 1047 and         1048, 1049 and 1050, 1063 and 1064, 1063 and 1065, 1063 and         1066, 1075 and 1076, 1091 and 1093, 1091 and 1096, 1093 and         1095, 1094 and 1097, 1098 and 1099, 1098 and 1100, 1099 and         1100, 1102 and 1103, 1104 and 1106, 1104 and 1107, 1104 and         1108, 1104 and 1109, 1104 and 1110, 1104 and 1111, 1104 and         1112, 1110 and 1111, 1112 and 1113, 1119 and 1120, 1124 and         1125, 1124 and 1126, 1125 and 1126, 1140 and 1141, 1142 and         1144, 1146 and 1151, 1147 and 1148, 1147 and 1149, 1153 and         1146, 1153 and 1147, 1155 and 1156, 1160 and 1161, 1165 and         1166, 1186 and 1187, 1188 and 1193, 1189 and 1193, 1191 and         1192, 1191 and 1193, 1191 and 1195, 1192 and 1193, 1192 and         1195, 1196 and 1197, 1206 and 1207, 1210 and 1218, 1211 and         1213, 1212 and 1213, 1213 and 1215, 1213 and 1216, 1213 and         1217, 1233 and 1238, 1242 and 1243, 1245 and 1246, 1263 and         1260, 1269 and 1279, 1270 and 1279, 1270 and 1282, 1271 and         1279, 1274 and 1279, 1278 and 1279, 1278 and 1281, 1279 and         1280, 1279 and 1281, 1279 and 1282, 1292 and 1293, 1296 and         1297, 1305 and 1314, 1306 and 1310, 1313 and 1321 or 1315 and         1322, or complements thereof.         240. The method of any one of paragraphs 200-239, wherein the         one or more genetic variations comprise a genetic variation         encoded by a CNV with at least 60%, at least 70%, at least 80%,         at least 90%, at least 95%, or at least 99% sequence identity to         any one of SEQ ID NOs 157, 2, 140, 65, 26, 14 or 45, or         complements thereof.         241. The method of paragraph 240, wherein the one or more         genetic variations comprise a genetic variation encoded by a CNV         with at least 60%, at least 70%, at least 80%, at least 90%, at         least 95%, or at least 99% sequence identity to any one of SEQ         ID NOs 2, 140, 65, 26, 14 or 45, or complements thereof.         242. The method of paragraph 240, wherein the one or more         genetic variations comprise a genetic variation encoded by a CNV         with at least 60%, at least 70%, at least 80%, at least 90%, at         least 95%, or at least 99% sequence identity to SEQ ID NO 157,         or a complement thereof.         243. The method of any one of paragraphs 200-242, wherein the         one or more genetic variations comprise a CNV-SNV pair         comprising a CNV and a single nucleotide variation (SNV),         wherein the SNV of the CNV-SNV pair is encoded by any one of SEQ         ID NOs 1301, 1173, 1107, 1104, 1199, 1225, 1086 or 1223, or         complements thereof.         244. The method of any one of paragraphs 200-243, wherein the         one or more genetic variations comprise a genetic variation         selected from the group consisting of one or more of the         following: chr8:145154222 G>A, chr2:163136505 C>G,         chr16:81942175 A>G, and chr8:61654298 T>A.         245. The method of any one of paragraphs 200-244, wherein the         one or more genetic variations disrupt or modulate one or more         of the following genes: PLCG2, POLE, LRBA, EPG5 and SHARPIN.         246. The method of any one of paragraphs 200-244, wherein the         one or more genetic variations disrupt or modulate one or more         of the following genes: PLCG2, CHD7, IFIH1, AP3B1, EPG5, PIK3CD,         LRBA and SHARPIN.         247. The method of any one of paragraphs 175-246, wherein the         gene encodes a transcript with a sequence that has at least 60%,         at least 70%, at least 80%, at least 90%, at least 95%, or at         least 99% sequence identity to any one of SEQ ID NOs 173-455 or         1500-2177, or complements thereof.         248. The method of paragraph 247, wherein the gene encodes a         transcript with a sequence that has at least 60%, at least 70%,         at least 80%, at least 90%, at least 95%, or at least 99%         sequence identity to any one of SEQ ID NOs 173-455, or         complements thereof.         249. The method of paragraph 247, wherein the gene encodes a         transcript with a sequence that has at least 60%, at least 70%,         at least 80%, at least 90%, at least 95%, or at least 99%         sequence identity to any one of SEQ ID NOs 1500-2177, or         complements thereof.         250. The method of any one of paragraphs 200-249, wherein the         one or more genetic variations comprise 2 or 3 or 4 or 5 or more         genetic variations.         251. The method of paragraph 250, wherein the one or more         genetic variations comprise 10 or more genetic variations.         252. The method of paragraph 250, wherein the one or more         genetic variations comprise 20 or more genetic variations.         253. The method of paragraph 250, wherein the one or more         genetic variations comprise 50 or more genetic variations.         254. The method of any one of paragraphs 175, 176, and 181 to         253, wherein the analyzing comprises microarray analysis, PCR,         sequencing, nucleic acid hybridization, or any combination         thereof.         255. The method of any one of paragraphs 177 to 179 and 182 to         253, wherein the genetic test result comprises a genetic test         result from a microarray analysis, PCR, sequencing, nucleic acid         hybridization, or any combination thereof.         256. The method of any one of paragraphs 180 and 182 to 253,         wherein the detecting comprises a microarray analysis, PCR,         sequencing, nucleic acid hybridization, or any combination         thereof.         257. The method of any one of paragraphs 254 to 256, wherein the         microarray analysis selected from the group consisting of a         Comparative Genomic Hybridization (CGH) array analysis and an         SNP array analysis.         258. The method of any one of paragraphs 254 to 256, wherein the         sequencing is selected from the group consisting of Massively         Parallel Signature Sequencing (MPSS), polony sequencing, 454         pyrosequencing, Illumina sequencing, Illumina (Solexa)         sequencing using 10× Genomics library preparation, SOLiD         sequencing, ion semiconductor sequencing, DNA nanoball         sequencing, heliscope single molecule sequencing, single         molecule real time (SMRT) sequencing, RNAP sequencing, Nanopore         DNA sequencing, sequencing by hybridization, and microfluidic         Sanger sequencing.         259. The method of any one of paragraphs 254, 257, and 258,         wherein the analyzing comprises analyzing a whole genome or a         whole exome of the subject.         260. The method of any one of paragraphs 254, 257, and 258,         wherein the analyzing comprises analyzing nucleic acid         information that has already been obtained for a whole genome or         a whole exome of the subject.         261. The method of paragraph 260, wherein the nucleic acid         information is obtained from an in silico analysis.         262. The method of any one of paragraphs 255, 257, and 258,         wherein the analyzing comprises analyzing a whole genome or a         whole exome of the subject.         263. The method of any one of paragraphs 255, 257, and 258,         wherein the analyzing comprises analyzing nucleic acid         information that has already been obtained for a whole genome or         a whole exome of the subject.         264. The method of paragraph 263, wherein the nucleic acid         information is obtained from an in silico analysis.         265. The method of any one of paragraphs 256 to 258, wherein the         detecting comprises analyzing a whole genome or a whole exome of         the subject.         266. The method of any one of paragraphs 256 to 258, wherein the         detecting comprises analyzing nucleic acid information that has         already been obtained for a whole genome or a whole exome of the         subject.         267. The method of paragraph 266, wherein the nucleic acid         information is obtained from an in silico analysis.         268. The method of any one of paragraphs 175 to 267, wherein the         subject is a human subject.         269. The method of any one of paragraphs 175 to 268, wherein the         polynucleic acid sample comprises a polynucleic acid from blood,         saliva, urine, serum, tears, skin, tissue, or hair of the         subject.         270. The method of any one of paragraphs 175 to 269, wherein the         method further comprises analyzing for a presence of JCV in a         biological sample from the subject.         271. The method of paragraph 270, wherein the analyzing for a         presence of JCV comprises contacting a JCV detection reagent to         the biological sample.         272. The method of paragraph 271, wherein the JCV detection         reagent is selected from the group consisting of an anti-JCV         antibody, a JCV specific primer, and combinations thereof.         273. A kit, comprising reagents for assaying a polynucleic acid         sample from a subject in need thereof for the presence of one or         more genetic variations that disrupt or modulate a gene of         GN1-GN490.         274. The kit of paragraph 273, wherein the reagents comprise at         least one contiguous oligonucleotide that hybridizes to a         fragment of the polynucleic acid sample.         275. The kit of paragraph 273 or 274, wherein the reagents         comprise at least one pair of oligonucleotides that hybridize to         opposite strands of a fragment of the polynucleic acid sample.         276. The kit of any one of paragraphs 273 to 275, wherein the         kit further comprises one or more immunosuppressive medications.         277. The kit of paragraph 276, wherein the one or more         immunosuppressive medications comprise a glucocorticoid,         cytostatic, antibody, drug acting on immunophilins, interferon,         opioid, TNF binding protein, mycophenolate, small biological         agent, or any combination thereof.         278. The kit of paragraph 276 or 277, wherein the one or more         immunosuppressive medications comprise a interferon beta-1a,         interferon beta-1b, glatiramer acetate, peginterferon beta-1a,         teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab,         mitoxantrone, rituximab, natalizumab, daclizumab, ocrelizumab,         diroximel fumarate or siponimod or any combination thereof.         279. The kit of paragraph 278, wherein the one or more         immunosuppressive medications comprise natalizumab.         280. The kit of any one of paragraphs 273 to 279, wherein the         kit further comprises a JCV detection reagent.         281. The method of paragraph 280, wherein the JCV detection         reagent is selected from the group consisting of an anti-JCV         antibody, a JCV specific primer, and combinations thereof.         282. The kit of any one of paragraphs 273 to 281, wherein the         kit further comprises a set of instructions for administration         of the one or more immunosuppressive medications.         283. The kit of any one of paragraphs 273 to 282, wherein the         one or more genetic variations comprise a point mutation,         polymorphism, single nucleotide polymorphisms (SNP), single         nucleotide variation (SNV), translocation, insertion, deletion,         amplification, inversion, interstitial deletion, copy number         variation (CNV), structural variation (SV), loss of         heterozygosity, or any combination thereof.         284. The kit of any one of paragraphs 273 to 283, wherein the         one or more genetic variations result in a loss of function of         the corresponding gene.         285. The kit of any one of paragraphs 273 to 284, wherein the         one or more genetic variations comprise 5 or more genetic         variations.         286. The kit of paragraph 285, wherein the one or more genetic         variations comprise 10 or more genetic variations.         287. The kit of paragraph 285, wherein the one or more genetic         variations comprise 20 or more genetic variations.         288. The kit of paragraph 285, wherein the one or more genetic         variations comprise 50 or more genetic variations.         289. The kit of any one of paragraphs 273 to 288, wherein the         subject is a human subject.         290. The kit of any one of paragraphs 273 to 289, wherein the         polynucleic acid sample comprises a polynucleic acid from blood,         saliva, urine, serum, tears, skin, tissue, or hair of the         subject.         291. A panel of polynucleic acids for detecting one or more         genetic variations that disrupt or modulate a gene of GN1-GN765,         wherein each polynucleic acid of the panel comprises a sequence         complementary to a sequence of one or more genetic variation or         complements thereof that disrupts or modulates a gene selected         from the group consisting of GN1-GN765.         292. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation encoded by a sequence with at least         60%, at least 70%, at least 80%, at least 90%, at least 95%, or         at least 99% sequence identity to SEQ ID NOs 1-172, 2200-2203,         or SRN1-SRN366, with 100% sequence identity to SEQ ID NOs         1000-1329, 3000-3274, or with at least 80% and less than 100%         sequence identity to GN1-GN765, or complements thereof.         293. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations are         encoded by a sequence with at least 60%, at least 70%, at least         80%, at least 90%, at least 95%, or at least 99% sequence         identity to SEQ ID NOs 2200-2203 or SRN364-SRN366, with 100%         sequence identity to SEQ ID NOs 3000-3274, or with at least 80%         and less than 100% sequence identity to GN491-GN765, or         complements thereof.         294. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation encoded by a CNV with at least 60%,         at least 70%, at least 80%, at least 90%, at least 95%, or at         least 99% sequence identity to SEQ ID NOs 1-172, or complements         thereof.         295. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation encoded by a CNV with at least 60%,         at least 70%, at least 80%, at least 90%, at least 95%, or at         least 99% sequence identity to SEQ ID NOs 2200-2203, or         complements thereof.         296. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation encoded by a CNV sub-region (SRN)         with at least 60%, at least 70%, at least 80%, at least 90%, at         least 95%, or at least 99% sequence identity to SRN1-SRN363, or         complements thereof.         297. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation encoded by a CNV sub-region (SRN)         with at least 60%, at least 70%, at least 80%, at least 90%, at         least 95%, or at least 99% sequence identity to SRN364-SRN366,         or complements thereof.         298. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation encoded by a single nucleotide         variation (SNV) with a sequence of any one of SEQ ID NOs:         1000-1329, or complements thereof.         299. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation encoded by a single nucleotide         variation (SNV) with a sequence of any one of SEQ ID NOs:         3000-3274, or complements thereof.         300. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation encoded by a sequence with at least         80% and less than 100% sequence identity to GN1-GN490, or         complements thereof.         301. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation encoded by a sequence with at least         80% and less than 100% sequence identity to GN491-GN765, or         complements thereof.         302. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation encoded by a single nucleotide         variation (SNV) with a sequence of any one of SEQ ID NO: 1000,         1001, 1002, 1009, 1010, 1011, 1012, 1014, 1016, 1017, 1019,         1020, 1028, 1032, 1033, 1034, 1035, 1036, 1037, 1040, 1041,         1043, 1051, 1054, 1056, 1057, 1058, 1059, 1061, 1062, 1063,         1066, 1068, 1069, 1070, 1071, 1073, 1074, 1075, 1076, 1077,         1078, 1080, 1082, 1084, 1090, 1092, 1098, 1099, 1100, 1101,         1104, 1107, 1114, 1116, 1118, 1121, 1122, 1123, 1125, 1126,         1127, 1128, 1129, 1130, 1131, 1133, 1135, 1136, 1137, 1138,         1142, 1146, 1147, 1148, 1150, 1152, 1154, 1157, 1160, 1161,         1165, 1166, 1167, 1168, 1169, 1171, 1174, 1175, 1176, 1177,         1178, 1179, 1180, 1181, 1182, 1183, 1184, 1193, 1194, 1200,         1201, 1202, 1203, 1204, 1208, 1219, 1220, 1221, 1222, 1226,         1227, 1228, 1229, 1230, 1231, 1232, 1235, 1239, 1247, 1248,         1249, 1250, 1251, 1252, 1254, 1255, 1256, 1259, 1260, 1261,         1263, 1264, 1266, 1267, 1273, 1278, 1279, 1283, 1284, 1286,         1287, 1289, 1290, 1291, 1299, 1300, 1301, 1304, 1311, 1327 or         1328, or complements thereof.         303. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation encoded by a single nucleotide         variation (SNV) with a sequence of any one of SEQ ID NO: 1011,         1020, 1028, 1032, 1034, 1035, 1036, 1040, 1056, 1069, 1073,         1077, 1101, 1114, 1123, 1125, 1126, 1127, 1135, 1142, 1146,         1147, 1148, 1152, 1154, 1157, 1167, 1174, 1184, 1193, 1194,         1203, 1208, 1221, 1222, 1229, 1235, 1252, 1255, 1256, 1259,         1260, 1261, 1263, 1273, 1278, 1279, 1284, 1287, 1289, 1299 or         1311, or complements thereof.         304. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation encoded by a single nucleotide         variation (SNV) with a sequence of any one of SEQ ID NO: 1000,         1001, 1002, 1009, 1010, 1012, 1014, 1016, 1017, 1019, 1033,         1037, 1041, 1043, 1051, 1054, 1057, 1058, 1059, 1061, 1062,         1063, 1066, 1068, 1070, 1071, 1074, 1075, 1076, 1078, 1080,         1082, 1084, 1090, 1092, 1098, 1099, 1100, 1104, 1107, 1116,         1118, 1121, 1122, 1128, 1129, 1130, 1131, 1133, 1136, 1137,         1138, 1146, 1147, 1150, 1152, 1160, 1161, 1165, 1166, 1168,         1169, 1171, 1175, 1176, 1177, 1178, 1179, 1180, 1181, 1182,         1183, 1200, 1201, 1202, 1204, 1219, 1220, 1226, 1227, 1228,         1230, 1231, 1232, 1239, 1247, 1248, 1249, 1250, 1251, 1252,         1254, 1264, 1266, 1267, 1278, 1279, 1283, 1286, 1290, 1291,         1300, 1301, 1304, 1327 or 1328, or complements thereof.         305. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation selected from the group consisting         of chr16:81942175 A>G, chr2:163136505 C>G, chr11:67818269 G>A,         chr22:23917192 G>T, chr20:3846397 C>T, chr8:145154222, G>A         chr8:61654298 T>A, chr3:39323163 A>C, chr4:151199080 G>A,         chr1:42047208 C>G, chr2:163124051 C>T, chr1:182554557 C>T,         chr8:145154824 A>C, chr20:62305450 C>T, chr22:23915745 G>A,         chr6:83884161 C>G, chr11:108202772 G>T, chr5:138856923 C>T,         chr16:1510535 C>T, chr20:3843027 C>A, chr12:122064788 G>GT,         chr16:7714909 C>T, chr18:56401523 C>T, chr1:92946625 G>C,         chr5:169081453 G>C, chr11:108117787 C>T, chr22:21235389 A>G,         chr19:4817657 C>T, chr10:1060218 G>A, chr21:30698953 T>G,         chr9:304628 G>A, chr19:7712287 G>C, chr10:90771767 G>A,         chr3:121415370 T>C, chr16:70503095 A>G, chr1:206945738 C>T,         chr5:156593120 C>T, chr4:27019452 C>T, chr1:155317682 C>T,         chr17:77926526 C>T, chr1:235840495 G>T, chr14:21993359 G>A,         chr8:61757805 C>T, chr15:91306241 G>A, chr16:50741791 C>T,         chr22:23915583 T>C, chr2:47205921 C>T, chr12:88900891 C>A,         chr3:142281353 C>G, chr11:108123551 C>T, chr1:207641950 C>T,         chr6:143092151 T>C, chr2:24431184 C>T, chr2:24432937 C>T,         chr9:312134 G>A, chr8:100205255 G>A, chr21:16339852 T>C, and any         combination thereof, wherein chromosome positions of the one or         more genetic variations are defined with respect to UCSC hg19.         306. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation selected from the group consisting         of chr16:81942175 A>G, chr2:163136505 C>G, chr11:67818269 G>A,         chr22:23917192 G>305, chr20:3846397 C>T, chr8:145154222, G>A         chr8:61654298 T>A, chr3:39323163 A>C, chr4:151199080 G>A,         chr1:42047208 C>G, chr2:163124051 C>T, chr1:182554557 C>T, and         any combination thereof, wherein chromosome positions of the one         or more genetic variations are defined with respect to UCSC         hg19.         307. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation selected from the group consisting         of chr8:145154824 A>C, chr20:62305450 C>T, chr22:23915745 G>A,         chr6:83884161 C>G, chr11:108202772 G>T, chr5:138856923 C>T,         chr16:1510535 C>T, chr20:3843027 C>A, chr12:122064788 G>GT,         chr16:7714909 C>T, chr18:56401523 C>T, chr1:92946625 G>C,         chr5:169081453 G>C, chr11:108117787 C>T, chr22:21235389 A>G,         chr19:4817657 C>T, chr10:1060218 G>A, chr21:30698953 T>G,         chr9:304628 G>A, chr19:7712287 G>C, chr10:90771767 G>A,         chr3:121415370 T>C, chr16:70503095 A>G, chr1:206945738 C>T,         chr5:156593120 C>T, chr4:27019452 C>T, chr1:155317682 C>T,         chr17:77926526 C>T, chr1:235840495 G>T, chr14:21993359 G>A,         chr8:61757805 C>T, chr15:91306241 G>A, chr16:50741791 C>T,         chr22:23915583 T>C, chr2:47205921 C>T, chr12:88900891 C>A,         chr3:142281353 C>G, chr11:108123551 C>T, chr1:207641950 C>T,         chr6:143092151 T>C, chr2:24431184 C>T, chr2:24432937 C>T,         chr9:312134 G>A, chr8:100205255 G>A, chr21:16339852 T>C, and any         combination thereof, wherein chromosome positions of the one or         more genetic variations are defined with respect to UCSC hg19.         308. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation selected from the group consisting         of chr1:196759282, C>T, chr4:126412634, C>G, chr10:75673748,         A>C, chr6:30675830, T>A, chr6:30680721, G>A, chr12:56385915,         GGGA>G, chr18:57103126, G>A, chr3:171321023, C>T, chr1:59131311,         G>T, chr22:31008867, T>C, chr2:74690378, C>T, chr17:7592168,         C>G, chr2:74690039, G>A, chr12:113448288, A>G, chr17:76130947,         G>T, chr2:15674686, T>C, chr2:15607842, T>C, chr14:94847262,         T>A, chr4:126412154, G>A, chr22:37271882, T>C, chr20:44640959,         G>A, chr17:8138569, C>G, chr12:113357237, G>C, chr12:113357209,         G>A, chr11:60893235, C>T, chr12:113357442, G>A, chr5:40964852,         A>C, chr14:35497285, T>C, chr19:55494157, G>A, and any         combination thereof, wherein chromosome positions of the one or         more genetic variations are defined with respect to UCSC hg19.         309. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation selected from the group consisting         of chr11:72145307, C>G, chr7:30491421, G>T, chr6:30673403, A>G,         chr19:44153248, T>C, chr17:43555253, A>G, chr2:188349523, A>G,         chr1:57409459, C>A, chr4:126241248, C>G, chr5:39311336, A>T,         chr17:76129619, C>T, chr4:110929301, T>C, chr3:11402163, G>A,         chr16:67694044, C>T, chr19:10395141, G>A, chr6:106740989, T>C,         chr1:183532364, T>A, chr22:35806756, G>A, chr4:110865044, G>C,         chr4:110864533, C>T, chr4:126238090, G>T, chr4:110932508, C>A,         chr6:31605016, T>C, chr7:92733766, C>A, chr18:29645930, A>T, and         any combination thereof, wherein chromosome positions of the one         or more genetic variations are defined with respect to UCSC         hg19.         310. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation selected from the group consisting         of chr21:45708278, G>A, chr11:108106443, T>A, chr1:57409459,         C>A, chr1:196918605, A>G, chr3:58191230, G>T, chr2:230579019,         G>A, chr9:137779251, G>A, chr1:27699670, AG>A, chr1:92946625,         G>C, chr1:42047208, C>G, chr2:163136505, C>G, chr22:23915583,         T>C, chr22:23915745, G>A, chr19:48643270, C>T, chr4:151793903,         T>C, chr1:160769595, AG>A, chr22:35806756, G>A, chr6:30673359,         T>G, chr6:3015818, G>A, chr6:51798908, C>T, chr16:81942175, A>G,         chr19:8564523, T>G, chr14:94847262, T>A, chr19:7712287, G>C,         chr6:32814942, C>T, chr6:32816772, C>A and chr11:67818269, G>A,         wherein chromosome positions of the one or more genetic         variations are defined with respect to UCSC hg19.         311. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation selected from the group consisting         of chr22:23915745, G>A, chr6:30673359, T>G, chr19:7712287, G>C,         chr9:137779251, G>A, chr22:23915583, T>C, chr22:35806756, G>A         and chr2:163136505, C>G. In some embodiments, the one or more         genetic variations comprise a genetic variation selected from         the group consisting of chr19:8564523, T>G, chr11:108106443,         T>A, chr6:32816772, C>A, chr6:32814942, C>T, chr16:81942175,         A>G, chr1:27699670, AG>A, chr2:230579019, G>A, chr14:94847262,         T>A and chr4:151793903, T>C, wherein chromosome positions of the         one or more genetic variations are defined with respect to UCSC         hg19.         312. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation selected from the group consisting         of chr22:23915745, G>A, chr6:30673359, T>G, chr19:7712287, G>C,         chr19:8564523, T>G, chr11:108106443, T>A, chr9:137779251, G>A,         chr22:23915583, T>C, chr22:35806756, G>A, chr2:163136505, C>G,         chr6:32816772, C>A, chr6:32814942, C>T, chr16:81942175, A>G,         chr1:27699670, AG>A, chr2:230579019, G>A, chr14:94847262 and         T>A, chr4:151793903, T>C, wherein chromosome positions of the         one or more genetic variations are defined with respect to UCSC         hg19.         313. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation selected from the group consisting         of chr1:160769595, AG>A, chr19:48643270, C>T, chr6:51798908,         C>T, chr21-45708278-G-A, chr1:92946625, G>C, chr1:196918605,         A>G, chr6:3015818, G>A, chr1:57409459, C>A, chr3:58191230, G>T         and chr16:81942175, A>G, wherein chromosome positions of the one         or more genetic variations are defined with respect to UCSC         hg19.         314. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation selected from the group consisting         of chr19:8564523, T>G, chr1:42047208, C>G and chr11:67818269,         G>A, wherein chromosome positions of the one or more genetic         variations are defined with respect to UCSC hg19.         315. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation selected from the group consisting         of chr1:160769595, AG>A, chr19:48643270, C>T, chr6:51798908,         C>T, chr21-45708278-G-A, chr1:92946625, G>C, chr1:196918605,         A>G, chr6:3015818, G>A, chr19:8564523, T>G, chr1:57409459, C>A,         chr3:58191230, G>T, chr16:81942175, A>G, chr1:42047208, C>G and         chr11:67818269, G>A, wherein chromosome positions of the one or         more genetic variations are defined with respect to UCSC hg19.         316. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation selected from the group consisting         of chr6:51798908, C>T, chr1:160769595, AG>A, chr1:196918605,         A>G, chr6:3015818, G>A, chr21-45708278-G-A, chr22:23915745, G>A,         chr11:67818269, G>A, chr11:108106443, T>A, chr6:30673359, T>G,         chr19:8564523, T>G, chr9:137779251, G>A, chr19:7712287, G>C and         chr16:81942175, A>G, wherein chromosome positions of the one or         more genetic variations are defined with respect to UCSC hg19.         317. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation selected from the group consisting         of chr6:32816772, C>A, chr6:32814942, C>T, chr1:92946625, G>C,         chr22:23915583, T>C, chr22:35806756, G>A, chr2:163136505, C>G,         chr1:27699670, AG>A and chr14:94847262, T>A, wherein chromosome         positions of the one or more genetic variations are defined with         respect to UCSC hg19.         318. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation selected from the group consisting         of chr6:51798908, C>T, chr1:160769595, AG>A, chr1:196918605,         A>G, chr6:3015818, G>A, chr21-45708278-G-A, chr22:23915745, G>A,         chr11:67818269, G>A, chr11:108106443, T>A, chr6:30673359, T>G,         chr19:8564523, T>G, chr9:137779251, G>A, chr19:7712287, G>C,         chr16:81942175, A>G, chr6:32816772, C>A, chr6:32814942, C>T,         chr1:92946625, G>C, chr22:23915583, T>C, chr22:35806756, G>A,         chr2:163136505, C>G, chr1:27699670, AG>A and chr14:94847262,         T>A, wherein chromosome positions of the one or more genetic         variations are defined with respect to UCSC hg19.         319. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation selected from the group consisting         of chr1:160769595, AG>A, chr6:51798908, C>T, chr21-45708278-G-A,         chr1:196918605, A>G, chr6:3015818, G>A, chr22:23915745, G>A,         chr19:8564523, T>G, chr6:30673359, T>G, chr9:137779251, G>A,         chr19:7712287, G>C, chr11:67818269, G>A and chr16:81942175, A>G,         wherein chromosome positions of the one or more genetic         variations are defined with respect to UCSC hg19.         320. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation selected from the group consisting         of chr19:48643270, C>T, chr22:35806756, G>A, chr1:92946625, G>C,         chr2:163136505, C>G, chr22:23915583, T>C, chr11:108106443, T>A,         chr6:32814942, C>T, chr6:32816772, C>A, chr1:27699670, AG>A,         chr4:151793903, T>C and chr14:94847262, T>A, wherein chromosome         positions of the one or more genetic variations are defined with         respect to UCSC hg19.         321. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation selected from the group consisting         of chr1:160769595, AG>A, chr6:51798908, C>T, chr21-45708278-G-A,         chr1:196918605, A>G, chr6:3015818, G>A, chr22:23915745, G>A,         chr19:8564523, T>G, chr6:30673359, T>G, chr9:137779251, G>A,         chr19:7712287, G>C, chr11:67818269, G>A, chr16:81942175, A>G,         chr19:48643270, C>T, chr22:35806756, G>A, chr1:92946625, G>C,         chr2:163136505, C>G, chr22:23915583, T>C, chr11:108106443, T>A,         chr6:32814942, C>T, chr6:32816772, C>A, chr1:27699670, AG>A,         chr4:151793903, T>C and chr14:94847262, T>A, wherein chromosome         positions of the one or more genetic variations are defined with         respect to UCSC hg19.         322. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations do not         comprise a genetic variation of chr2:163136505, C>G, wherein         chromosome positions of the one or more genetic variations are         defined with respect to UCSC hg19.         323. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations do not         comprise a genetic variation of chr22:23915745, G>A, wherein         chromosome positions of the one or more genetic variations are         defined with respect to UCSC hg19.         324. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations do not         comprise a genetic variation of chr16:81942175, A>G, wherein         chromosome positions of the one or more genetic variations are         defined with respect to UCSC hg19.         325. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations do not         comprise a genetic variation of chr19:7712287, G>C, wherein         chromosome positions of the one or more genetic variations are         defined with respect to UCSC hg19.         326. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations do not         comprise a genetic variation of chr11:67818269, G>A, wherein         chromosome positions of the one or more genetic variations are         defined with respect to UCSC hg19.         327. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations do not         comprise a genetic variation of chr2:163136505, C>G;         chr22:23915745, G>A; chr16:81942175, A>G; chr19:7712287, G>C;         and chr11:67818269, G>A, wherein chromosome positions of the one         or more genetic variations are defined with respect to UCSC         hg19.         328. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the SNV is a heterozygous SNV.         329. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the SNV is a homozygous SNV.         330. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a pair of single nucleotide variations (SNVs), wherein         the pair of SNVs are encoded by any one of SEQ ID NO pairs: 1003         and 1004, 1003 and 1005, 1006 and 1007, 1024 and 1025, 1030 and         1031, 1047 and 1048, 1049 and 1050, 1063 and 1064, 1063 and         1065, 1063 and 1066, 1075 and 1076, 1091 and 1093, 1091 and         1096, 1093 and 1095, 1094 and 1097, 1098 and 1099, 1098 and         1100, 1099 and 1100, 1102 and 1103, 1104 and 1106, 1104 and         1107, 1104 and 1108, 1104 and 1109, 1104 and 1110, 1104 and         1111, 1104 and 1112, 1110 and 1111, 1112 and 1113, 1119 and         1120, 1124 and 1125, 1124 and 1126, 1125 and 1126, 1140 and         1141, 1142 and 1144, 1146 and 1151, 1147 and 1148, 1147 and         1149, 1153 and 1146, 1153 and 1147, 1155 and 1156, 1160 and         1161, 1165 and 1166, 1186 and 1187, 1188 and 1193, 1189 and         1193, 1191 and 1192, 1191 and 1193, 1191 and 1195, 1192 and         1193, 1192 and 1195, 1196 and 1197, 1206 and 1207, 1210 and         1218, 1211 and 1213, 1212 and 1213, 1213 and 1215, 1213 and         1216, 1213 and 1217, 1233 and 1238, 1242 and 1243, 1245 and         1246, 1263 and 1260, 1269 and 1279, 1270 and 1279, 1270 and         1282, 1271 and 1279, 1274 and 1279, 1278 and 1279, 1278 and         1281, 1279 and 1280, 1279 and 1281, 1279 and 1282, 1292 and         1293, 1296 and 1297, 1305 and 1314, 1306 and 1310, 1313 and 1321         or 1315 and 1322, or complements thereof.         331. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation encoded by a CNV with at least 60%,         at least 70%, at least 80%, at least 90%, at least 95%, or at         least 99% sequence identity to any one of SEQ ID NOs 157, 2,         140, 65, 26, 14 or 45, or complements thereof.         332. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation encoded by a CNV with at least 60%,         at least 70%, at least 80%, at least 90%, at least 95%, or at         least 99% sequence identity to any one of SEQ ID NOs 2, 140, 65,         26, 14 or 45, or complements thereof.         333. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation encoded by a CNV with at least 60%,         at least 70%, at least 80%, at least 90%, at least 95%, or at         least 99% sequence identity to SEQ ID NO 157, or a complement         thereof.         334. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a CNV and a single nucleotide variations (SNV), wherein         SNVs is encoded by any one of SEQ ID NOs 1301, 1173, 1107, 1104,         1199, 1225, 1086 or 1223, or complements thereof.         335. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise a genetic variation selected from the group consisting         of one or more of the following: chr8:145154222 G>A,         chr2:163136505 C>G, chr16:81942175 A>G, and chr8:61654298 T>A,         wherein chromosome positions of the one or more genetic         variations are defined with respect to UCSC hg19.         336. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         disrupt or modulate one or more of the following genes: PLCG2,         POLE, LRBA, EPG5 and SHARPIN.         337. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         disrupt or modulate one or more of the following genes: PLCG2,         CHD7, IFIH1, AP3B1, EPG5, PIK3CD, LRBA and SHARPIN.         338. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the gene encodes a transcript with a         sequence that has at least 60%, at least 70%, at least 80%, at         least 90%, at least 95%, or at least 99% sequence identity to         any one of SEQ ID NOs 173-455, 1500-2177, 2204-2215, 2300-2893,         or complements thereof.         339. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the gene encodes a transcript with a         sequence that has at least 60%, at least 70%, at least 80%, at         least 90%, at least 95%, or at least 99% sequence identity to         any one of SEQ ID NOs 173-455, or complements thereof.         340. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the gene encodes a transcript with a         sequence that has at least 60%, at least 70%, at least 80%, at         least 90%, at least 95%, or at least 99% sequence identity to         any one of SEQ ID NOs 1500-2177, or complements thereof.         341. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the gene encodes a transcript with a         sequence that has at least 60%, at least 70%, at least 80%, at         least 90%, at least 95%, or at least 99% sequence identity to         any one of SEQ ID NOs 2204-2215, or complements thereof.         342. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the gene encodes a transcript with a         sequence that has at least 60%, at least 70%, at least 80%, at         least 90%, at least 95%, or at least 99% sequence identity to         any one of SEQ ID NOs 2300-2893, or complements thereof.         343. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the one or more genetic variations         comprise at least 5, at least 10, at least 20, or at least 50         genetic variations.         344. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein panel of polynucleic acids comprises at         least 5, at least 10, at least 20, or at least 50 polynucleic         acids.         345. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the gene comprises a gene selected from         the group consisting of gene numbers (GNs) GN1-GN156 in Table 3.         346. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the gene comprises a gene selected from         the group consisting of gene numbers (GNs) GN157-GN490 in Table         6.         347. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the corresponding gene comprises a gene         selected from the group consisting of gene numbers (GNs)         GN491-GN492 in Table 29.         348. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the corresponding gene comprises a gene         selected from the group consisting of gene numbers (GNs)         GN493-GN762 in Table 31.         349. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the corresponding gene comprises a gene         selected from the group consisting of gene numbers (GNs)         GN763-GN765 in Table 48.         350. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the corresponding gene comprises a gene         selected from Tables 34-40, and 42.         351. The kit of any one of paragraphs 273-290 or the panel of         paragraph 291, wherein the gene comprises a gene selected from         the group consisting of PLCG2, RBCK1, EPG5, IL17F, SHARPIN,         PRF1, JAGN1, TAP1, POLE, LRBA, EHF, IL12B, ATL2, NHEJ1, LYST,         HIVEP1, AP3B1, TNFRSF10A, PIK3CD, PNP, MCEE, DOCK2 and ALG12.         352. A method to predict an adverse responsiveness of a subject         to a therapy, the method comprising     -   (a) detecting one or more genetic variations that disrupt or         modulate a gene of GN1-GN765 in a polynucleic acid sample from         the subject; and     -   (b) using that detection as a biomarker for predicting a         response of the subject to the therapy to be adverse, wherein         the therapy is an immunosuppressive therapy comprising one or         more immunosuppressive medications.         353. A method of screening for a PML biomarker comprising     -   (a) obtaining biological samples from subjects with PML;     -   (b) screening the biological samples to obtain nucleic acid         information;     -   (c) detecting one or more genetic variations that disrupt or         modulate a gene of GN1-GN765 in a polynucleic acid sample from a         subject suspected of having PML; and     -   (d) using that detection as a biomarker for predicting a         response of the subject to the therapy to be adverse, wherein         the therapy is an immunosuppressive therapy comprising one or         more immunosuppressive medications.         354. A method of screening for a PML biomarker comprising     -   (a) obtaining biological samples from subjects with PML;     -   (b) screening the biological samples to obtain nucleic acid         information;     -   (c) confirming each biological sample is not a duplicate of any         other biological sample based on the nucleic acid information;     -   (d) detecting one or more genetic variations that disrupt or         modulate a gene of GN1-GN765 in a polynucleic acid sample from a         subject suspected of having PML; and     -   (e) using that detection as a biomarker for predicting a         response of the subject to the therapy to be adverse, wherein         the therapy is an immunosuppressive therapy comprising one or         more immunosuppressive medications.         355. A method of screening for a PML biomarker comprising     -   (a) obtaining biological samples from subjects with PML;     -   (b) screening the biological samples to obtain nucleic acid         information;     -   (c) determining a sex genotype for each biological sample based         on the nucleic acid information;     -   (d) confirming the sex genotype of each sample is the same as a         sex phenotype of the subject from the subjects with PML;     -   (e) detecting one or more genetic variations that disrupt or         modulate a gene of GN1-GN765 in a polynucleic acid sample from a         subject suspected of having PML; and     -   (f) using that detection as a biomarker for predicting a         response of the subject to the therapy to be adverse, wherein         the therapy is an immunosuppressive therapy comprising one or         more immunosuppressive medications.         356. A method of treating a condition in a subject in need of         immunosuppressive therapy, comprising: administering a         therapeutically effective amount of one or more         immunosuppressive medications to the subject, wherein the         subject has a decreased risk of progressive multifocal         leukoencephalopathy (PML) due to an infection of the brain by         John Cunningham virus (JCV), and wherein the subject's decreased         risk is due to the absence of one or more genetic variations         that disrupt or modulate a gene, wherein a subject with the         disrupted or modulated gene has increased risk of progressive         multifocal leukoencephalopathy (PML) due to an infection of the         brain by John Cunningham virus (JCV).         357. A method of treating a condition in a subject in need of         natalizumab therapy, comprising: administering a therapeutically         effective amount of natalizumab to the subject, wherein the         subject has a decreased risk of progressive multifocal         leukoencephalopathy (PML) due to an infection of the brain by         John Cunningham virus (JCV), wherein the subject's decreased         risk is associated with an absence of one or more genetic         variations in the subject, wherein the subject has been tested         for a presence of the one or more genetic variations with a         genetic assay and has been identified as not having the one or         more genetic variations, wherein the one or more genetic         variations have an odds ratio (OR) of 3 or more, and wherein the         OR is: [D_(D)/D_(N)]/[N_(D)/N_(N)], wherein: D_(D) is the number         of subjects in a diseased cohort of subjects with the one or         more genetic variations; D_(N) is the number of subjects in the         diseased cohort without the one or more genetic variations;         N_(D) is the number of subjects in a non-diseased cohort of         subjects with the one or more genetic variations; and N_(N) is         the number of subjects in the non-diseased cohort without the         one or more genetic variations, wherein the diseased cohort of         subjects have PML, and wherein the non-diseased cohort of         subjects do not have PML.         358. The method of paragraph 357, wherein the one or more         genetic variations have an OR of at least 4, 5, 6, 7, 8, 9, or         10.         359. The method of paragraph 357, wherein the one or more         genetic variations occur in one or more immune function-related         genes.         360. A method of treating a condition in a subject in need of         immunosuppressive therapy, comprising: administering a         therapeutically effective amount of one or more         immunosuppressive medications to the subject, wherein the         subject has a decreased risk of progressive multifocal         leukoencephalopathy (PML) due to an infection of the brain by         John Cunningham virus (JCV), and wherein the subject's decreased         risk is due to the absence of one or more genetic variations         that disrupt or modulates a corresponding gene according to         Tables 3, 6, 29, 31 and 48.         361. The method of any one of paragraphs 352-358, wherein the         one or more immunosuppressive medications comprise a         glucocorticoid, cytostatic, antibody, drug acting on         immunophilins, interferon, opioid, TNF binding protein,         mycophenolate, small biological agent, small molecule, organic         compound, or any combination thereof.         362. The method of any one of paragraphs 352-361, wherein the         one or more immunosuppressive medications comprise abatacept,         adalimumab, alefacept, alemtuzumab, anakinra, azathioprine,         belimumab, bendamustine, bevacizumab, bortezomib, brentuximab         vedotin, capecitabine, carboplatin, cetuximab, chlorambucil,         cladribine, cyclophosphamide, cyclosporine, daclizumab,         doxorubicin, diroximel fumarate, efalizumab, etanercept,         etoposide, fludarabine, gemcitabine, ibritumomab tiuxetan,         imatinib, infliximab, lenalidomide, methotrexate, mycophenolate         mofetil, natalizumab, oxaliplatin, rituximab, tocilizumab,         tofacitinib, ustekinumab, vedolizumab, vincristine, belatacept,         cytotoxic chemotherapy, corticosteroids, antithymocyte Ig,         basiliximab, muromonab-CD3, mycophenolic acid,         prednisone/prednisolone, sirolimus, tacrolimus, dimethyl         fumarate, fingolimod, ruxolitinib, interferon beta-1a,         interferon beta-1b, glatiramer acetate, peginterferon beta-1a,         teriflunomide, mitoxantrone, ocrelizumab, asparaginase,         bleomycin, busulfan, carmustine, certolizumab, ibrutinib,         idarubicin, idelalisib, hydrocortisone, ifosfamide, levamisole,         mercaptopurine, mizoribine, obinutuzumab, ofatumumab,         tegafur/gimeracil/oteracil, thiotepa, vinblastine, vincristine,         aldesleukin, azacitidine, atezolizumab, blinatumomab,         carfilzomib, cisplatin, cytarabine, daratumumab, dasatinib,         denosumab, dexamethasone, epirubicin, everolimus, fluorouracil,         golimumab, hydroxychloroquine sulfate, hydroxyurea, interferon         alfa-2, interferon gamma-1, ipilimumab, ixazomib, lapatinib,         leflunomide, melphalan, methylprednisone, nivolumab,         osimertinib, paclitaxel, pazopanib, pembrolizumab, pemetrexed,         pentostatin, pomalidomide, ponatinib, sorafenib, sunitinib,         temozolomide, thalidomide, venetoclax, vorinostat,         acalabrutinib, agatolimod sodium, alisertib, alvespimycin         hydrochloride, alvocidib, aminocamptothecin, andecaliximab,         anifrolumab, apatinib, apelisib, atacicept, avelumab, bafetinib,         baminercept, baricitinib, becatecarin, begelomab, bemcentinib,         betalutin with lilotomab, bimekizumab, binimetinib, bryostatin         1, bucillamine, buparlisib, canakinumab, carfilzomib, cediranib         maleate, cemiplimab, cerdulatinib, chidamide, cilengitide,         cirmtuzumab, clazakizumab, clioquinol, defactinib, defibrotide,         denosumab, diacerein, dinaciclib, durvalumab, duvelisib,         duvortuxizumab, encorafenib, entinostat, entospletinib,         enzastaurin, epacadostat, epratuzumab, eritoran tetrasodium,         eftilagimod alpha, evobrutinib, filgotinib, firategrast,         fontolizumab, forodesine hydrochloride, fostamatinib,         galunisertib, ganetespib, ganitumab, gemtuzumab ozogamicin,         gerilimzumab, glasdegib, glassia, glembatumumab vedotin,         glesatinib, guadecitabine, ibudilast, iguratimod, imexon,         inotuzumab ozogamicin, irofulven, isatuximab, ispinesib,         itacitinib, laquinimod, laromustine, ld-aminopterin, lenvatinib,         lirilumab, lonafamib, lumiliximab, masitinib, mavrilimumab,         methoxsalen, milatuzumab, mocetinostat, monalizumab,         mosunetuzumab, motesanib diphosphate, moxetumomab pasudotox,         namilumab, navitoclax, neihulizumab, neurovax, niraparib,         obatoclax mesylate, oblimersen sodium, olokizumab, opicinumab,         oprelvekin, otelixizumab, ozanimod, pacritinib, palifermin,         panobinostat, peficitinib, pegsunercept (peg stnf-ri),         penclomedine, perifosine, pevonedistat, pexidartinib,         picoplatin, pidilizumab, pivanex, pixantrone, pleneva, plovamer         acetate, polatuzumab vedotin, ponesimod, pyroxamide, recombinant         il-12, relatlimab, rhigf-1, rhigm22, rigosertib, rilonacept,         sarilumab, secukinumab, selumetinib, sintilimab, siponimod,         siplizumab, sirukumab, sitravatinib, sonidegib, sotrastaurin         acetate, tabalumab, talabostat mesylate, talacotuzumab,         tanespimycin, temsirolimus, tenalisib, terameprocol, thiarabine,         tipifarnib, tirabrutinib, tislelizumab, tivozanib, tregalizumab,         tremelimumab, treosulfan, ublituximab, umbralisib, upadacitinib,         urelumab, varlilumab, vatelizumab, veliparib, veltuzumab,         vinorelbine ditartrate, visilizumab, vismodegib, vistusertib,         vosaroxin, and ziv-aflibercept, or any combination thereof.         363. The method of any one of paragraphs 352-362, wherein the         one or more immunosuppressive medications comprise natalizumab.         364. The method of any one of paragraphs 358-362, wherein the         one or more immunosuppressive medications comprise an antibody         molecule or a fragment thereof.         365. The method of paragraph 364, wherein the antibody molecule         or a fragment thereof is a humanized recombinant antibody         molecule or a fragment thereof.         366. The method of paragraph 364, wherein the antibody molecule         or a fragment thereof is a humanized recombinant IgG4κ         monoclonal antibody molecule or a fragment thereof.         367. The method of paragraph 364, wherein the antibody molecule         or a fragment thereof is produced in murine myeloma cells.         368. The method of paragraph 364, wherein the antibody molecule         or a fragment thereof binds an integrin.         369. The method of paragraph 368, wherein the integrin is         expressed on surface of a leukocyte.         370. The method of paragraph 369, wherein the leukocyte is not a         neutrophil.         371. The method of paragraph 364, wherein the antibody molecule         or a fragment thereof binds α4β1 integrin, α4β7 integrin, or         both.         372. The method of paragraph 364, wherein the antibody molecule         or a fragment thereof binds α4-subunit of α4β1 integrin, α4β7         integrin, or both.         373. The method of paragraph 364, wherein the antibody molecule         or a fragment thereof inhibits α4-mediated adhesion of a         leukocyte to its receptor.         374. The method of any one of paragraphs 364-373, wherein the         antibody molecule or a fragment thereof comprises a sequence         that has at least 60%, 70%, 80%, 90%, 95%, or 100% sequence         identity to SEQ ID NO. 3275.         375. The method of any one of paragraphs 364-374, wherein the         antibody molecule or a fragment thereof comprises a sequence         that has at least 60%, 70%, 80%, 90%, 95%, or 100% sequence         identity to SEQ ID NO. 3276.         376. The method of any one of paragraphs 352-375, wherein the         condition is multiple sclerosis or Crohn's disease.         377. The method of paragraph 376, wherein the condition is a         relapsing form of multiple sclerosis.         378. The method of paragraph 362, wherein the natalizumab is         administered via intravenous infusion.         379. The method of paragraph 362, wherein about 100 mg to about         500 mg of the natalizumab is administered.         380. The method of any one of paragraphs 352-379, wherein the         one or more genetic variations are associated with a risk of         developing PML in a polynucleic acid sample from the subject.         381. The method of any one of paragraphs 352-380, wherein the         method comprises testing the subject for a genetic         predisposition for PML with a genetic assay.         382. The method of paragraph 381, wherein the genetic assay has         a diagnostic yield of at least 20%.         383. The method of any one of paragraphs 352-382, wherein the         one or more genetic variations disrupt or modulate a         corresponding gene according to Tables 13-18.         384. The method of any one of paragraphs 352-383, wherein the         one or more genetic variations disrupt or modulate a         corresponding gene according to Tables 19-24.         385. The method of any one of paragraphs 352-383, wherein the         one or more genetic variations disrupt or modulate a         corresponding gene according to Tables 34-40, and 42.         386. The method of any one of paragraphs 352-384, wherein the         one or more genetic variations comprises a first genetic         variation and a second genetic variation, wherein the first         genetic variation disrupts or modulates a corresponding gene         according to Tables 3, 6, 29, 31 and 48, and wherein the second         genetic variation disrupts or modulates a corresponding gene         according to Tables 25A, 25B, and 26.         387. The method of any one of paragraphs 352-386, wherein the         one or more genetic variations disrupt or modulate a         corresponding gene selected from the group consisting of Homo         sapiens chromodomain helicase DNA binding protein 7 (CHD7), Homo         sapiens interferon induced with helicase C domain 1 (IFIH1),         Homo sapiens immunoglobulin lambda like polypeptide 1 (IGLL1),         Homo sapiens mitochondrial antiviral signaling protein (MAVS),         Homo sapiens phospholipase C gamma 2 (PLCG2), Homo sapiens         SHANK-associated RH domain interactor (SHARPIN), Homo sapiens         T-cell immune regulator 1, ATPase H+ transporting V0 subunit a3         (TCIRG1), and any combination thereof.         388. The method of any one of paragraphs 352-387, wherein the         one or more genetic variations comprise chr8:61654298 T>A,         chr2:163136505 C>G, chr22:23917192 G>T, chr20:3846397 C>T,         chr16:81942175 A>G, chr8:145154222 G>A, chr11:67818269 G>A,         chr8:145154824 A>C, chr22:23915745 G>A, chr20:3843027 C>A, or         any combination thereof, wherein the chromosome positions are         defined with respect to UCSC hg19.         389. The method of any one of paragraphs 352-388, wherein the         corresponding gene comprises a gene selected from the group         consisting of gene numbers (GNs) GN1-GN765 in Table 3.         390. The method of any one of paragraphs 352-388, wherein the         corresponding gene comprises a gene selected from the group         consisting of gene numbers (GNs) GN1-GN490 in Table 6.         391. The method of any one of paragraphs 352-388, wherein the         corresponding gene comprises a gene selected from the group         consisting of gene numbers (GNs) GN491-GN492 in Table 29.         392. The method of any one of paragraphs 352-388, wherein the         corresponding gene comprises a gene selected from the group         consisting of gene numbers (GNs) GN493-GN762 in Table 31.         393. The method of any one of paragraphs 352-388, wherein the         corresponding gene comprises a gene selected from the group         consisting of gene numbers (GNs) GN763-GN765 in Table 48.         394. The method of any one of paragraphs 352-388, wherein the         corresponding gene comprises a gene selected from Tables 34-40,         and 42.         395. The method of any one of paragraphs 352-389, wherein the         corresponding gene comprises a gene selected from the group         consisting of gene numbers (GNs) GN1-GN241, GN243-GN369, and         GN371-GN490.         396. The method of any one of paragraphs 352-395, wherein the         one or more genetic variations are encoded by a sequence with at         least 60% sequence identity to SEQ ID NOs 1-172, 2200-2203 or         SRN1-SRN366, with 100% sequence identity to SEQ ID NOs         1000-1329, 3000-3274, or with at least 80% and less than 100%         sequence identity to GN1-GN765, or complements thereof.         397. The method of any one of paragraphs 352-395, wherein the         one or more genetic variations are encoded by a sequence with at         least 60%, at least 70%, at least 80%, at least 90%, at least         95%, or at least 99% sequence identity to SEQ ID NOs 2200-2203         or SRN364-SRN366, with 100% sequence identity to SEQ ID NOs         3000-3274, or with at least 80% and less than 100% sequence         identity to GN491-GN765, or complements thereof.         398. The method of any one of paragraphs 352-396, wherein the         one or more genetic variations comprise a genetic variation         encoded by a CNV with at least 60% sequence identity to SEQ ID         NOs 1-172, or complements thereof.         399. The method of any one of paragraphs 352-396, wherein the         one or more genetic variations comprise a genetic variation         encoded by a CNV with at least 60%, at least 70%, at least 80%,         at least 90%, at least 95%, or at least 99% sequence identity to         SEQ ID NOs 2200-2203, or complements thereof.         400. The method of any one of paragraphs 352-398, wherein the         one or more genetic variations comprise a genetic variation         encoded by a CNV sub-region (SRN) with at least 60% sequence         identity to SRN1-SRN363, or complements thereof.         401. The method of any one of paragraphs 352-398, wherein the         one or more genetic variations comprise a genetic variation         encoded by a CNV sub-region (SRN) with at least 60%, at least         70%, at least 80%, at least 90%, at least 95%, or at least 99%         sequence identity to SRN364-SRN366, or complements thereof.         402. The method of any one of paragraphs 352-400, wherein the         one or more genetic variations comprise a genetic variation         encoded by a single nucleotide variation (SNV) with a sequence         of any one of SEQ ID NOs: 1000-1329, or complements thereof.         403. The method of any one of paragraphs 352-400, wherein the         one or more genetic variations comprise a genetic variation         encoded by a single nucleotide variation (SNV) with a sequence         of any one of SEQ ID NOs: 3000-3274, or complements thereof.         404. The method of paragraph 381, wherein the genetic assay         comprises microarray analysis, PCR, sequencing, nucleic acid         hybridization, or any combination thereof.         405. The method of any one of paragraphs 352-404, wherein the         method comprises testing the subject with a JCV-antibody test, a         CD62L test, or a CSF IgM oligoclonal bands test.         406. The method of paragraph 405, wherein the method comprises         testing the subject with the JCV-antibody test, wherein the         JCV-antibody test does not detect a presence of JCV.         407. The method of paragraph 406, wherein the JCV-antibody test         comprises contacting a JCV detection reagent to a biological         sample from the subject.         408. The method of paragraph 407, wherein the JCV detection         reagent is selected from the group consisting of an anti-JCV         antibody, a JCV specific primer, and combinations thereof.         409. The method of any one of paragraphs 352-408, wherein the         subject is identified as not having one or more genetic         variations that disrupt or modulate a corresponding gene         according to Tables 3, 6, 29, 31 and 48.         410. The method of any one of paragraphs 352-408, wherein the         subject is identified as not having one or more genetic         variations that disrupt or modulate a corresponding gene         according to Tables 29 and 31.         411. A kit, comprising reagents for assaying a polynucleic acid         sample from a subject in need thereof for the presence of one or         more genetic variations that disrupt or modulate a gene of         GN1-GN765.         412. The kit of paragraph 411, comprising reagents for assaying         the polynucleic acid sample from the subject in need thereof for         the presence of the one or more genetic variations that disrupt         or modulate the gene of GN491-GN765.         413. A method of treating multiple sclerosis or Crohn's disease         in a subject in need thereof, comprising: administering a         therapeutically effective amount of natalizumab to the subject,         wherein the subject has been tested for a genetic predisposition         for PML with a genetic assay and has been identified as not         having the genetic predisposition for PML, wherein the genetic         assay has a diagnostic yield of at least 20%.         414. The method of paragraph 413, wherein the one or more         immunosuppressive medications comprise natalizumab.         415. The method of paragraph 413 or 414, wherein the method         further comprises testing the subject with a JCV-antibody test.         416. The method of any one of paragraphs 413-415, wherein the         genetic assay tests the subject for the presence of one or more         genetic variations that disrupt or modulate a corresponding gene         according to Tables 3, 6, 29, 31 and 48. 417. The method of any         one of paragraphs 413-415, wherein the genetic assay tests the         subject for the presence of one or more genetic variations that         disrupt or modulate a corresponding gene according to Tables 29         and 31.         418. A method of identifying a subject as not having a risk of         developing PML, comprising:     -   (a) analyzing a polynucleic acid sample from the subject for one         or more genetic variations that disrupt or modulate a         corresponding gene according to Tables 3, 6, 29, 31 and 48,         wherein a genetic variation of the one or more genetic         variations that disrupt or modulate a corresponding gene         according to Tables 3, 6, 29, 31 and 48 is not present in the         polynucleic acid sample; and     -   (b) identifying the subject as not having a risk of developing         PML.         419. The method of any one of paragraphs 357-418, wherein the         diseased cohort of subjects, the non-diseased cohort of         subjects, or both cohorts of subjects are ethnically matched.         420. The method of any one of paragraphs 364-419, wherein the         antibody molecule or fragment thereof comprises at least one         antibody heavy chain, or an α4-binding fragment thereof,         comprising non-human CDRs at positions 31-35 (CDR1), 50-65         (CDR2) and 95-102 (CDR3) (Kabat numbering) from a mouse anti-α4         antibody and having non-human residues at framework positions         27-30 (Kabat numbering), wherein said positions 27-30 have the         amino acid sequence Phe 27, Asn 28, Ile 29 and Lys 30.         421. The method of paragraph 420, wherein the antibody molecule         or fragment thereof comprises at least one antibody light chain,         or an α4-binding fragment thereof, comprising: a light chain         (LC) CDR1 with an amino acid sequence of SEQ ID NO.: 3277         (KTSQDINKYMA), a LC CDR2 with an amino acid sequence of SEQ ID         NO.: 3278 (YTSALQP), and a LC CDR3 with an amino acid sequence         of SEQ ID NO.: 3279 (LQYDNLWT).         422. The method of paragraph 420, wherein the antibody molecule         or fragment thereof comprises at least one antibody light chain,         or an α4-binding fragment thereof, comprising: a light chain         (LC) CDR1 with an amino acid sequence of SEQ ID NO.: 3280         (QASQDIIKYLN), a LC CDR2 with an amino acid sequence of SEQ ID         NO.: 3281 (EASNLQA), and a LC CDR3 with an amino acid sequence         of SEQ ID NO.: 3282 (QQYQSLPYT).         423. The method of paragraph 420, wherein the antibody molecule         or fragment thereof comprises at least one antibody light chain,         or an α4-binding fragment thereof, comprising: a light chain         (LC) CDR1 with an amino acid sequence of SEQ ID NO.: 3283         (KASQSVTNDVA), a LC CDR2 with an amino acid sequence of SEQ ID         NO.: 3284 (YASNRYT), and a LC CDR3 with an amino acid sequence         of SEQ ID NO.: 3285 (QQDYSSPYT).         424. The method of any one of paragraphs 420-423, wherein the         antibody molecule or fragment thereof comprises at least one         antibody heavy chain, or an α4-binding fragment thereof,         comprising: a heavy chain (HC) CDR1 with an amino acid sequence         of SEQ ID NO.: 3286 (DTYIH), a HC CDR2 with an amino acid         sequence of SEQ ID NO.: 3287 (RIDPANGYTKYDPKFQG), and a HC CDR3         with an amino acid sequence of SEQ ID NO.: 3288         (EGYYGNYGVYAMDY).         425. The method of any one of paragraphs 420-423, wherein the         antibody molecule or fragment thereof comprises at least one         antibody heavy chain, or an α4-binding fragment thereof,         comprising: a heavy chain (HC) CDR1 with an amino acid sequence         of SEQ ID NO.: 3289 (DTYMH), a HC CDR2 with an amino acid         sequence of SEQ ID NO.: 3290 (RIDPASGDTKYDPKFQV), and a HC CDR3         with an amino acid sequence of SEQ ID NO.: 3291 (DGMWVSTGYALDF).         426. The method of any one of paragraphs 420-425, wherein the         antibody molecule or fragment thereof comprises a humanized         heavy chain, or an α4-binding fragment thereof, comprising: a         variable heavy chain region selected from the group consisting         of:

SEQ ID NO.: 3292 (MDWTWRVFCLLAVAPGAHSQVQLQESGPGLVRPSQTLSLTCTVSGFNIK DTYMHWVRQPPGRGLEWIGRIDPASGDTKYDPKFQVKATITADTSSNQFS LRLSSVTAADTAVYYCADGMWVSTGYALDFWGQGTTVTVSSGES), SEQ ID NO.: 3293 (QVQLQESGPGLVRPSQTLSLTCTVSGFNIKDTYMHWVRQPPGRGLEWIG RIDPASGDTKYDPKFQVRVTMLVDTSSNQFSLRLSSVTSEDTAVYYCADG MWVSTGYALDFWGQGTTVTVSSGES), SEQ ID NO.: 3294 (MDWTWRVFCLLAVAPGAHSQVQLQESGPGLVRPSQTLSLTCTVSGFNIK DTYMHWVKQRPGRGLEWIGRIDPASGDTKYDPKFQVRVTMLVDTSSNQFS LRLSSVTAADTAVYYCADGMWVSTGYALDFWGQGTTVTVSSGES), SEQ ID NO.: 3295 (MDWTWRVFCLLAVAPGAHSQVQLQESGPGLVRPSQTLSLTCTASGFNIK DTYMHWVRQPPGRGLEWIGRIDPASGDTKYDPKFQVRVTMLVDTSSNQFS LRLSSVTAADTAVYYCADGMWVSTGYALDFWGQGTTVTVSSGES), and SEQ ID NO.: 3296 (QVQLVQSGAEVKKPGASVKVSCKASGFNIKDTYIHWVRQAPGQRLEWMG RIDPANGYTKYDPKFQGRVTITADTSASTAYMELSSLRSEDTAVYYCARE GYYGNYGVYAMDWGQGTLVTVSS). 427. The method of any one of paragraphs 420-426, wherein the antibody molecule or fragment thereof comprises a humanized light chain, or an α4-binding fragment thereof, comprising a variable light chain region selected from the group consisting of:

SEQ ID NO.: 3297 (MGWSCIILFLVATATGVHSDIQLTQSPSSLSASVGDRVTITCKASQSVT NDVAWYQQKPGKAPKLLIYYASNRYTGVPSRFSGSGSGTDFTFTISSLQP EDIATYYCQQDYSSPYTFGQGTKVEIKRK), SEQ ID NO.: 3298 (MGWSCIILFLVATATGVHSSIVMTQSPSSLSASVGDRVTITCKASQSVT NDVAWYQQKPGKAPKLLIYYASNRYTGVPDRFSGSGYGTDFTFTISSLQP EDIATYYCQQDYSSPYTFGQGTKVEIKRK), SEQ ID NO.: 3299 (MGWSCIILFLVATATGVHSDIQMTQSPSSLSASVGDRVTITCKASQSVT NDVAWYQQKPGKAPKLLIYYASNRYTGVPDRFSGSGYGTDFTFTISSLQP EDIATYYCQQDYSSPYTFGQGTKVEIKRK), and SEQ ID NO.: 3300 (DIQMTQSPSSLSASVGDRVTITCKTSQDINKYMAWYQQTPGKAPRLLIH YTSALQPGIPSRFSGSGSGRDYTFTISSLQPEDIATYYCLQYDNLWTFGQ GTKVEIKRTV). 428. A method of treating a condition in a subject in need of natalizumab therapy, comprising: administering a therapeutically effective amount of natalizumab to the subject, wherein the subject has a decreased risk of progressive multifocal leukoencephalopathy (PML) due to an infection of the brain by John Cunningham virus (JCV), wherein the subject's decreased risk is associated with an absence of one or more genetic variations in the subject, wherein the subject has been tested for a presence of the one or more genetic variations with a genetic assay and has been identified as not having the one or more genetic variations selected from Table 43. 429. A method of treating a condition in a subject in need of natalizumab therapy, comprising: administering a therapeutically effective amount of natalizumab to the subject, wherein the subject has a decreased risk of progressive multifocal leukoencephalopathy (PML) due to an infection of the brain by John Cunningham virus (JCV), wherein the subject's decreased risk is associated with a presence of one or more genetic variations in the subject, wherein the subject has been tested for a presence of the one or more genetic variations with a genetic assay and has been identified as having the one or more genetic variations selected from Table 44. 

What is claimed is:
 1. A method of treating a condition in a subject in need of immunosuppressive therapy, comprising: administering a therapeutically effective amount of an immunosuppressive agent to the subject, wherein the subject has a decreased risk of progressive multifocal leukoencephalopathy (PML) due to an infection of the brain by John Cunningham virus (JCV), wherein the subject's decreased risk is associated with the absence of one or more genetic variations in the subject, wherein the subject has been tested for a presence of the one or more genetic variations with a genetic assay and has been identified as not having the one or more genetic variations; wherein the one or more genetic variations have an odds ratio (OR) of 2 or more, and wherein the OR is: [D_(D)/D_(N)]/[N_(D)/N_(N)], wherein: D_(D) is the number of subjects in a diseased cohort of subjects with the one or more genetic variations; D_(N) the number of subjects in the diseased cohort without the one or more genetic variations; N_(D) is the number of subjects in a non-diseased cohort of subjects with the one or more genetic variations; and N_(N) is the number of subjects in the non-diseased cohort without the one or more genetic variations; and wherein the diseased cohort of subjects have PML and the non-diseased cohort of subjects do not have PML.
 2. The method of claim 1, wherein the condition is multiple sclerosis or a relapsing form of multiple sclerosis.
 3. The method of claim 1, wherein the condition is Crohn's disease.
 4. The method of claim 1, wherein the immunosuppressive agent is interferon beta-1a, interferon beta-1b, glatiramer acetate, peginterferon beta-1a, teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone, rituximab, natalizumab, daclizumab, ocrelizumab, diroximel fumarate, siponimod or any combination thereof.
 5. The method of claim 1, wherein the one or more genetic variations comprises chr21:45708278 G>A, chr14:94847262 T>A, chr1:57409459 C>A, chr22:35806756 G>A, chr11:108106443 T>A, chr1:196918605 A>G, chr3:58191230 G>T, chr2:230579019 G>A, chr9:137779251 G>A, chr1:27699670 AG>A, chr19:48643270 C>T, chr4:151793903 T>C, chr1:160769595 AG>A, chr6:30673359 T>G, chr6:3015818 G>A, chr19:8564523 T>G, chr6:32814942 C>T or chr6:32816772 C>A; wherein chromosome positions of the one or more genetic variations are defined with respect to UCSC hg19.
 6. The method of claim 1, wherein a first genetic variation of the one or more genetic variations comprises chr21:45708278 G>A, chr14:94847262 T>A, chr1:57409459 C>A, chr22:35806756 G>A, chr11:108106443 T>A, chr1:196918605 A>G, chr3:58191230 G>T, chr2:230579019 G>A, chr9:137779251 G>A, chr1:27699670 AG>A, chr19:48643270 C>T, chr4:151793903 T>C, chr1:160769595 AG>A, chr6:30673359 T>G, chr6:3015818 G>A, chr19:8564523 T>G, chr6:32814942 C>T or chr6:32816772 C>A; and wherein a second genetic variation of the one or more genetic variations comprises chr2:163136505 C>G, chr11:67818269 G>A, chr22-23915745 G>A, chr16:81942175 A>G, chr19:7712287 G>C, chr1:92946625-G-C, chr1:42047208 C>G, chr22:23915583 T>C, chr6:51798908 C>T, wherein the chromosome positions are defined with respect to UCSC hg19.
 7. The method of claim 1, wherein the one or more genetic variations disrupts or modulates a gene selected from the group consisting of SERPINA1, AIRE, C8B, MCM5, CFHR2, DNASE1L3, FCN2, FCN3, LY9, MDC1 and PRAM1.
 8. The method of claim 7, wherein a first genetic variation of the one or more genetic variations disrupts or modulates a gene selected from SERPINA1, AIRE, C8B, MCM5, CFHR2, DNASE1L3, FCN2, FCN3, LY9, MDC1 and PRAM1; and wherein a second genetic variation of the one or more genetic variations disrupts or modulates a gene selected from IFIH1, TCIRG1, IGLL1, PLCG2, STXBP2, GFI1, HIVEP3, PKHD1, ATM, DNER, LIG1, LRBA, TAP1 and NQO2.
 9. The method of claim 1, wherein the one or more genetic variations comprise an SNV in a gene selected from the group consisting of SERPINA1, AIRE, C8B, MCM5, CFHR2, DNASE1L3, FCN2, LY9, MDC1, PRAM1, FCN3 and NQO2.
 10. The method of claim 9, wherein a first genetic variation of the one or more genetic variations comprise an SNV in a gene selected from the group consisting of SERPINA1, AIRE, C8B, MCM5, CFHR2, DNASE1L3, FCN2, LY9, MDC1, PRAM1, FCN3 and NQO2; and wherein a second genetic variation of the one or more genetic variations disrupts or modulates a gene selected from IFIH1, TCIRG1, IGLL1, PLCG2, STXBP2, GFI1, HIVEP3, PKHD1, ATM, DNER, LIG1, LRBA and TAP1.
 11. The method of claim 1, wherein the diseased cohort of subjects, the non-diseased cohort of subjects, or both cohorts of subjects are ethnically matched.
 12. The method of claim 1, wherein the one or more genetic variations have an odds ratio (OR) of 6 or more.
 13. The method of claim 1, wherein the subject has been identified as not having one or more other genetic variations that disrupt or modulate a corresponding gene according to Tables 1, 3, 6-10, 28A, 29, 31, 34-36, 47 and
 48. 14. The method of claim 1, wherein the subject is identified as not having one or more other genetic variations that disrupt or modulate a corresponding gene according to Tables 19-24, 40 and
 42. 15. The method of claim 1, wherein the subject has been tested with a JCV-antibody test, a CD62L test, or a CSF IgM oligoclonal bands test.
 16. The method of claim 1, wherein the one or more genetic variations comprise two or more genetic variations.
 17. The method of claim 1, wherein the method further comprises testing the subject for the presence of the one or more genetic variations with the genetic assay prior to the administering.
 18. The method of claim 17, wherein the genetic assay comprises microarray analysis, PCR, sequencing, nucleic acid hybridization, or any combination thereof.
 19. The method of claim 17, wherein the one or more genetic variations disrupt or modulate one or more immune response-related genes or immune pathway related genes.
 20. The method of claim 17, wherein prior to testing the subject for the presence of the one or more genetic variations with the genetic assay the method further comprises obtaining biological samples from subjects with PML and (a) confirming each biological sample is not a duplicate of any other biological sample based on nucleic acid information of the biological samples or (b) determining a sex genotype for each biological sample based on nucleic acid information of the biological samples, and confirming the sex genotype of each biological sample is the same as a sex phenotype of the subject with PML from which the biological sample was obtained. 